Variant chr2-38989304-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_005633.4(SOS1):c.3357C>T(p.Thr1119=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000654 in 1,604,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SOS1
NM_005633.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.02

Variant links:

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]

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 2-38989304-G-A is Benign according to our data. Variant chr2-38989304-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38989304-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.3357C>T	p.Thr1119=	synonymous_variant	21/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.3357C>T	p.Thr1119=	synonymous_variant	21/23	1	NM_005633.4	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250202

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000606

AC:

AN:

1452514

Hom.:

Cov.:

AF XY:

0.0000650

AC XY:

AN XY:

723112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000743

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000112

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000117

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000110

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2016	Variant summary: The SOS1 c.3357C>T (p.Thr1119Thr) variant causes a synonymous change involving a conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing and ESE finder predicting that this variant may create a new affect ESE site of, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 9/118630 (1/13175, frequency: 0.0000759), predominantly in the European (Non-Finnish) cohort, 8/65198 (1/8149), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333 (0.00003). Therefore, suggesting that the variant is a common polymorphism found in population(s) of European (Non-Finnish) origin. A publication cites the variant to have been found in at least one affected individual, although with limited information (ie lack of co-occurrence cosegregation data). In addition, a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 16, 2015

p.Thr1119Thr in exon 21 of SOS1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 8/65198 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs373319212). -

Noonan syndrome 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

- -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2020

This alteration is classified as likely 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

Genome-Nilou Lab

- -

RASopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.8

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 10

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over