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NM_152594.3(SPRED1):c.124G>A (p.Val42Ile)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(1);Likely benign(2);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Jan 29, 2020)
Last evaluated:
Dec 31, 2019
Accession:
VCV000047965.5
Variation ID:
47965
Description:
single nucleotide variant
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NM_152594.3(SPRED1):c.124G>A (p.Val42Ile)

Allele ID
57129
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q14
Genomic location
15: 38299464 (GRCh38) GRCh38 UCSC
15: 38591665 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000015.10:g.38299464G>A
NC_000015.9:g.38591665G>A
NG_008980.1:g.51614G>A
NM_152594.3:c.124G>A MANE Select NP_689807.1:p.Val42Ile missense
Protein change
V42I
Other names
p.V42I:GTC>ATC
Canonical SPDI
NC_000015.10:38299463:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00160 (A)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00061
Exome Aggregation Consortium (ExAC) 0.00069
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00022
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
1000 Genomes Project 0.00160
Links
ClinGen: CA142270
dbSNP: rs147204964
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter Jul 26, 2012 RCV000041238.4
Likely benign 1 criteria provided, single submitter Dec 31, 2019 RCV001086208.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Apr 17, 2017 RCV000586558.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
SPRED1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
413 435

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Benign
(Apr 17, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699957.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: The SPRED1 c.124G>A (p.Val42Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the WH1/EVH1 … (more)
Likely benign
(Jul 26, 2012)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000064929.6
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (1)
Comment:
Val42Ile in exon 02 of SPRED1: The Val42Ile variant in SPRED1 was reported in on e individual with Legius syndrome (Spencer 2011). Furthermore, this variant … (more)
Likely benign
(Dec 31, 2019)
criteria provided, single submitter
Method: clinical testing
Legius syndrome
Allele origin: germline
Invitae
Accession: SCV000767050.3
Submitted: (Jan 29, 2020)
Evidence details
Uncertain significance
(Aug 19, 2016)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000209136.11
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The V42I variant in the SPRED1 gene has not been reported previously as a disease-causing variant nor as a benign polymorphism, to our knowledge. This … (more)

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. Hirata Y The Journal of biological chemistry 2016 PMID: 26635368
SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Pasmant E Oncogene 2015 PMID: 24469042
Review and update of SPRED1 mutations causing Legius syndrome. Brems H Human mutation 2012 PMID: 22753041
Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. Spencer E American journal of medical genetics. Part A 2011 PMID: 21548021

Text-mined citations for rs147204964...

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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 Nov 27, 2021