rs753151750

chr14-50118759-G-Achr14-50118759-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006939.4(SOS2):c.3584C>T(p.Ala1195Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000354 in 1,612,426 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1195G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.75

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08176425).
• BP6: Variant 14-50118759-G-A is Benign according to our data. Variant chr14-50118759-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421233.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.3584C>T	p.Ala1195Val	missense_variant	23/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.3584C>T	p.Ala1195Val	missense_variant	23/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.3485C>T	p.Ala1162Val	missense_variant	22/22	1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151394 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249676 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135160

Gnomad AFR exome AF: 0.00

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: 0.0000710

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1460916 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 726744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151510 Hom.: 0 Cov.: 30 AF XY: 0.0000541 AC XY: 4 AN XY: 73974

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SOS2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2019	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

The p.A1195V variant (also known as c.3584C>T), located in coding exon 23 of the SOS2 gene, results from a C to T substitution at nucleotide position 3584. The alanine at codon 1195 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Noonan syndrome 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Benign	0.89
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.67	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.18
Sift	Benign	0.71	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0020	B;.
Vest4		0.038
MVP		0.16
MPC		0.19
ClinPred		0.15	T
GERP RS		5.0
Varity_R		0.078
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753151750; hg19: chr14-50585477;