rs139290271

Positions:

• chr2-39051259-A-G

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.749T>C (p.Val250Ala) variant in the SOS1 gene is 0.089% for African chromosomes by the Exome Aggregation Consortium (15/10392 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA136183/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:8
• Conservation: PhyloP100: 4.05

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.749T>C	p.Val250Ala	missense_variant	6/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.749T>C	p.Val250Ala	missense_variant	6/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251268 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135818

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000480 AC: 70 AN: 1459094 Hom.: 0 Cov.: 29 AF XY: 0.0000427 AC XY: 31 AN XY: 726104

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74476

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.000657

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2018	Variant summary: SOS1 c.749T>C (p.Val250Ala) results in a non-conservative amino acid change located in the Dbl homology (DH) domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 277018 control chromosomes. The observed variant frequency is approximately 6 fold above the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.749T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (2x), likely benign (3x), and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 01, 2011	Variant classified as Uncertain Significance - Favor Benign. The Val250Ala varia nt has not been previously reported in the literature. However, this variant was identified in one other Black individual tested by our laboratory and that indi vidual's reportedly unaffected mother. This variant has now been identified in 2 /75 (2.7%) of Black probands tested by our laboratory. In addition, Val at posit ion 250 is not conserved across evolutionarily distinct species and computationa l analyses (PolyPhen2, SIFT, AlignGVGD) predict that this variant will not impac t the normal function of the protein. It should be noted that the sensitivity an d specificity of these computational programs has not been determined by our lab oratory. Therefore, the clinical significance of this variant cannot be determin ed conclusively at this time; however, based upon the arguments described above we would lean towards a more likely benign role. -

RASopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.749T>C (p.Val250Ala) variant in the SOS1 gene is 0.089% for African chromosomes by the Exome Aggregation Consortium (15/10392 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). -

Noonan syndrome and Noonan-related syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

SOS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.35	T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.90	N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.14
MVP		0.33
MPC		0.68
ClinPred		0.030	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.22

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: rs139290271; hg19: chr2-39278400;