VCV000198348.26 - ClinVar

NM_025074.7(FRAS1):c.9806G>A (p.Arg3269Gln)

Interpretation:: Benign/Likely benign
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 11
First in ClinVar:: Jun 28, 2015
Most recent Submission:: Jan 21, 2023
Last evaluated:: Jun 9, 2022
Accession:: VCV000198348.26
Variation ID:: 198348
Description:: single nucleotide variant

NM_025074.7(FRAS1):c.9806G>A (p.Arg3269Gln)

Allele ID

195509

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

4q21.21

Genomic location

4: 78511299 (GRCh38) GRCh38 UCSC

4: 79432453 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_025074.7:c.9806G>A MANE Select	NP_079350.5:p.Arg3269Gln	missense
NC_000004.12:g.78511299G>A
NC_000004.11:g.79432453G>A
NG_015812.1:g.458730G>A
NG_015812.2:g.458730G>A

... more HGVS ... less HGVS

Protein change

R3269Q

Other names

Canonical SPDI

NC_000004.12:78511298:G:A

Functional consequence

Global minor allele frequency (GMAF)

0.00140 (A)

Allele frequency

1000 Genomes Project 0.00140

Exome Aggregation Consortium (ExAC) 0.00567

The Genome Aggregation Database (gnomAD) 0.00526

The Genome Aggregation Database (gnomAD) 0.00592

Trans-Omics for Precision Medicine (TOPMed) 0.00581

The Genome Aggregation Database (gnomAD), exomes 0.00518

Trans-Omics for Precision Medicine (TOPMed) 0.00628

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00695

Links

ClinGen: CA203377

dbSNP: rs61729366

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not specified	Benign/Likely benign	4	criteria provided, multiple submitters, no conflicts	Jun 9, 2022	RCV000179644.10
Fraser syndrome 1	Likely benign	3	criteria provided, multiple submitters, no conflicts	Apr 3, 2022	RCV000315339.7
not provided	Benign/Likely benign	3	criteria provided, multiple submitters, no conflicts	Dec 16, 2021	RCV000872220.15
Congenital diaphragmatic hernia	risk factor	1	no assertion criteria provided	Nov 9, 2016	RCV000577951.2

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
FRAS1		-	-	GRCh38 GRCh37	872	899

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Likely benign (Sep 14, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory,University of Chicago Accession: SCV000594881.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015
Benign (Jan 21, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins NTD LLC (GA) Accession: SCV000231924.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FRAS1 http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=4&from=79432453&to=79432453 Number of individuals with the variant: 2 Zygosity: 2 Single Heterozygote Sex: mixed
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fraser syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services,Illumina Accession: SCV000451296.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Dec 16, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Invitae Accession: SCV001014005.3 First in ClinVar: Dec 17, 2019 Last updated: May 16, 2022
Benign (Jun 09, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002555803.1 First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022	Comment: Variant summary: FRAS1 c.9806G>A (p.Arg3269Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: FRAS1 c.9806G>A (p.Arg3269Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 246530 control chromosomes (gnomAD), predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (Apr 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fraser syndrome 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002802550.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Nov 01, 2020)	criteria provided, single submitter (Praxis fuer Humangenetik Tuebingen - Variant Classification Criteria) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001502463.10 First in ClinVar: Mar 14, 2021 Last updated: Jan 21, 2023	Number of individuals with the variant: 1
risk factor (Nov 09, 2016)	no assertion criteria provided Method: research	Congenital diaphragmatic hernia Affected status: yes Allele origin: inherited	Daryl Scott Lab,Baylor College of Medicine Accession: SCV000484668.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Clinical Features: Ventricular septal defect (present) , Pectus excavatum (present) , Bilateral hydronephrosis (present) , Cryptorchidism (present) , Inguinal hernia (present) Zygosity: 1 Single Heterozygote
Likely benign (-)	no assertion criteria provided Method: clinical testing	Fraser syndrome 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734360.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798770.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929395.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Variant summary: FRAS1 c.9806G>A (p.Arg3269Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 246530 control chromosomes (gnomAD), predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FRAS1	-	-	-	-
http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=4&from=79432453&to=79432453	-	-	-	-

Text-mined citations for rs61729366...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 21, 2023

ClinVar Genomic variation as it relates to human health

NM_025074.7(FRAS1):c.9806G>A (p.Arg3269Gln)

NM_025074.7(FRAS1):c.9806G>A (p.Arg3269Gln)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs61729366...