2-38987571-T-C

Position:

chr2-38987571-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_005633.4(SOS1):c.3412A>G(p.Ile1138Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000299 in 1,573,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 4.35

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117449164).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000303 (43/1421196) while in subpopulation EAS AF= 0.000584 (23/39398). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.3412A>G	p.Ile1138Val	missense_variant	22/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.3412A>G	p.Ile1138Val	missense_variant	22/23	1	NM_005633.4	ENSP00000384675	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000288

AC:

AN:

242652

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

131202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.0000338

Gnomad FIN exome

AF:

0.0000936

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1421196

Hom.:

Cov.:

AF XY:

0.0000339

AC XY:

AN XY:

708928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000584

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2018	The c.3412 A>G (I1138V ) variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/268,480 global alleles (0.003%) in large population cohorts (Lek et al., 2016). Multiple in silico splice prediction programs predict that the c.3412 A>G substitution creates a cryptic splice donor site upstream of the canonical splice donor site in intron 22, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the actual effect of this sequence change in this individual is unknown.If expressed and translated, the I1138V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 07, 2018

Variant summary: SOS1 c.3412A>G (p.Ile1138Val) results in a conservative amino acid change in 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 3e-05 in 268480 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions (3e-05 vs 3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3412A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Noonan syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2022

The p.I1138V variant (also known as c.3412A>G), located in coding exon 22 of the SOS1 gene, results from an A to G substitution at nucleotide position 3412. The isoleucine at codon 1138 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a Noonan syndrome cohort; however, clinical details were limited (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is well conserved in available vertebrate species. 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. -

Fibromatosis, gingival, 1

Uncertain:1

Uncertain significance, 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 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.30

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.20

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.93

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.0080

B;B;.

Vest4

0.34

MutPred

0.29

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MVP

0.31

MPC

0.082

ClinPred

0.074

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.099

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