NM_001365902.3(NFIX):c.1456del (p.Arg486fs) AND Marshall-Smith syndrome

Germline classification:: Pathogenic (2 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001072120.3

Allele description [Variation Report for NM_001365902.3(NFIX):c.1456del (p.Arg486fs)]

NM_001365902.3(NFIX):c.1456del (p.Arg486fs)

Gene:

NFIX:nuclear factor I X [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_001365902.3(NFIX):c.1456del (p.Arg486fs)

HGVS:

NC_000019.10:g.13090352del
NG_032925.2:g.99583del
NM_001271043.2:c.1480del
NM_001271044.3:c.1284del
NM_001365902.3:c.1456delMANE SELECT
NM_001365982.2:c.1185del
NM_001365983.2:c.1167del
NM_001365984.2:c.1453del
NM_001365985.2:c.1305del
NM_001378404.1:c.1432del
NM_001378405.1:c.1504del
NM_002501.4:c.1308del
NP_001257972.1:p.Arg494fs
NP_001257973.1:p.Thr430fs
NP_001352831.1:p.Arg486fs
NP_001352911.1:p.Thr397fs
NP_001352912.1:p.Thr391fs
NP_001352913.1:p.Arg485fs
NP_001352914.1:p.Thr437fs
NP_001365333.1:p.Arg478fs
NP_001365334.1:p.Arg502fs
NP_002492.2:p.Thr438fs
NC_000019.9:g.13201166del

Protein change:

R478fs

Links:

OMIM: 164005.0013; dbSNP: rs2018058219

NCBI 1000 Genomes Browser:

rs2018058219

Molecular consequence:

NM_001271043.2:c.1480del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001271044.3:c.1284del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365902.3:c.1456del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365982.2:c.1185del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365983.2:c.1167del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365984.2:c.1453del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365985.2:c.1305del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378404.1:c.1432del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001378405.1:c.1504del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002501.4:c.1308del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Marshall-Smith syndrome (MRSHSS)
Identifiers:: MONDO: MONDO:0011244; MedGen: C0265211; Orphanet: 561; OMIM: 602535

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001237463	OMIM	no assertion criteria provided	Pathogenic (Apr 14, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004048013	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001237463

OMIM

no assertion criteria provided

Pathogenic
(Apr 14, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004048013

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.

Schanze D, Neubauer D, Cormier-Daire V, Delrue MA, Dieux-Coeslier A, Hasegawa T, Holmberg EE, Koenig R, Krueger G, Schanze I, Seemanova E, Shaw AC, Vogt J, Volleth M, Reis A, Meinecke P, Hennekam RC, Zenker M.

Hum Mutat. 2014 Sep;35(9):1092-100. doi: 10.1002/humu.22603. Epub 2014 Jul 8.

PubMed [citation]

PMID:: 24924640

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001237463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated male patients (P6 and P12) with Marshall-Smith syndrome (MRSHSS; 602535), Schanze et al. (2014) identified heterozygosity for a 1-bp deletion (c.1456delC, ENST00000592199) in exon 10 of the NFIX gene, causing a frameshift predicted to result in a premature termination codon (Arg486GlyfsTer6). The mutation occurred de novo in both probands.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048013.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The frame shift c.1456del(p.Arg486GlyfsTer6) variant in NFIX gene has been reported in heterozygous state in individuals affected with Marshall-Smith syndrome (MRSHSS) (Schanze, Denny et al.,2014). The variant is novel (not in any individuals) in gnomAD Exomes and in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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