rs143166880

Positions:

chr14-50118840-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006939.4(SOS2):c.3503C>A(p.Ser1168Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,385,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.28

Variant links:

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010614395).

BP6

Variant 14-50118840-G-T is Benign according to our data. Variant chr14-50118840-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 475753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4 linkuse as main transcript	c.3503C>A	p.Ser1168Tyr	missense_variant	23/23	ENST00000216373.10	NP_008870.2	Q07890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10 linkuse as main transcript	c.3503C>A	p.Ser1168Tyr	missense_variant	23/23	1	NM_006939.4	ENSP00000216373.5		Q07890-1
SOS2	ENST00000543680.5 linkuse as main transcript	c.3404C>A	p.Ser1135Tyr	missense_variant	22/22	1		ENSP00000445328.1		Q07890-2

Frequencies

GnomAD3 genomes

AF:

0.000370

AC:

AN:

121494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000913

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000647

AC:

AN:

139168

Hom.:

AF XY:

0.0000522

AC XY:

AN XY:

76668

show subpopulations

Gnomad AFR exome

AF:

0.000747

Gnomad AMR exome

AF:

0.0000804

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000230

AC:

AN:

1263498

Hom.:

Cov.:

AF XY:

0.0000163

AC XY:

AN XY:

615376

show subpopulations

Gnomad4 AFR exome

AF:

0.000857

Gnomad4 AMR exome

AF:

0.000125

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:

0.00

Gnomad4 OTH exome

AF:

0.0000391

GnomAD4 genome

AF:

0.000370

AC:

AN:

121598

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

58888

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.0000911

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000381

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.000466

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000671

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 9

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

SOS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2022

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). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.097

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.21

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.69

N;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0

B;.

Vest4

0.076

MVP

0.27

MPC

0.24

ClinPred

0.019

GERP RS

3.2

Varity_R

0.051

gMVP

0.17

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

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