rs140811086

chr2-39013505-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005633.4(SOS1):c.2122G>A(p.Ala708Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,612,550 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A708V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (60 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 0.385

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009043574).
• BP6: Variant 2-39013505-C-T is Benign according to our data. Variant chr2-39013505-C-T is described in ClinVar as [Benign]. Clinvar id is 40697.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39013505-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00279 (424/151844) while in subpopulation AMR AF= 0.0258 (393/15240). AF 95% confidence interval is 0.0237. There are 11 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.2122G>A	p.Ala708Thr	missense_variant	13/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.2122G>A	p.Ala708Thr	missense_variant	13/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 151754 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00692 AC: 1737 AN: 250922 Hom.: 49 AF XY: 0.00533 AC XY: 722 AN XY: 135578

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0490

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: 0.0000353

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00149 AC: 2179 AN: 1460706 Hom.: 60 Cov.: 30 AF XY: 0.00132 AC XY: 956 AN XY: 726694

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0464

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: 0.0000162

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00279 AC: 424 AN: 151844 Hom.: 11 Cov.: 32 AF XY: 0.00334 AC XY: 248 AN XY: 74198

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.0258

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.000432 Hom.: 1

Bravo AF: 0.00473

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00535 AC: 650

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2009	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 27153395, 21387466, 27535533, 22585553, 21340158) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 22, 2015	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.2122G>A (p.Ala708Thr) variant in the SOS1 gene is 5.13% for Latino chromosomes by the Exome Aggregation Consortium (633/11554 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). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Noonan syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Joubert syndrome 3 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Ala708Thr variant in SOS1 has only been previously reported in individuals without Noonan syndrome but has been reported in association with Noonan syndrome (PMID: 22585553, 21340158), and has been identified in >5% of Latino chromosomes and 23 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant Noonan syndrome. -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 28, 2019

- -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2018

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. -

Fibromatosis, gingival, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.52	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;.
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.015	B;B;.
Vest4		0.20
MVP		0.84
MPC		0.57
ClinPred		0.011	T
GERP RS		4.9
Varity_R		0.22
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140811086; hg19: chr2-39240646;