rs56219475

Variant names:

• chr2-39013966-G-A
• rs56219475
• NM_005633.4:c.1964C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1964C>T (p.Pro655Leu) variant in the SOS1 gene is 1.153% (803/65674) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136088/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (74 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel B:19
• Conservation: PhyloP100: 5.44

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1964C>T	p.Pro655Leu	missense_variant	Exon 12 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1964C>T	p.Pro655Leu	missense_variant	Exon 12 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes AF: 0.00762 AC: 1158 AN: 151948 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00466

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00745 AC: 1861 AN: 249736 Hom.: 10 AF XY: 0.00756 AC XY: 1021 AN XY: 135084

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00860 AC: 12493 AN: 1452776 Hom.: 74 Cov.: 28 AF XY: 0.00838 AC XY: 6061 AN XY: 723268

Gnomad4 AFR exome AF: 0.00231

Gnomad4 AMR exome AF: 0.00419

Gnomad4 ASJ exome AF: 0.00388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000813

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00999

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00762 AC: 1158 AN: 152066 Hom.: 11 Cov.: 32 AF XY: 0.00767 AC XY: 570 AN XY: 74340

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00968 Hom.: 12

Bravo AF: 0.00730

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00145 AC: 5 AN: 3474

EpiCase AF: 0.0106

EpiControl AF: 0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOS1: BS1, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17143282, 20981092, 23487764, 17143285, 27153395, 32514133) -

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Apr 18, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.1964C>T (p.Pro655Leu) variant in the SOS1 gene is 1.153% (803/65674) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Feb 02, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Aug 24, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Apr 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;D;D
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.066	B;B;.
Vest4		0.28
MVP		0.32
MPC		0.59
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.34
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56219475; hg19: chr2-39241107;