Genetic Variant NM_005633.4:c.1352C>G (chr2-39023076-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The NM_005633.4(SOS1):c.1352C>G(p.Thr451Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T451K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.84

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain PH (size 104) in uniprot entity SOS1_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_005633.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-39023076-G-T is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.1352C>G	p.Thr451Arg	missense_variant	Exon 10 of 23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 link	c.1352C>G	p.Thr451Arg	missense_variant	Exon 10 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251022

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00000547

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 24, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1352C>G (p.Thr451Arg) in SOS1 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within Pleckstrin homology (PH) domain functional domain that is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.000008 (1/121314 chrs tested), exclusively in individuals of Latino origin (0.00008; 1/11576 chrs tested). The latter frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in SOS1 gene (0.00003). The variant is present in a control population dataset of gmomAD exclusively in individuals of Latino origin: 0.000196 (7/35710chrs), suggesting that it may be a rare ethnic-specific functional polymorphism. However, since the data set is still in beta mode, this data was not captured in pbGP. The variant has not, to our knowledge, been identified in patients with NSRD via published reports but was cited as VUS by a reputable database/diagnostic laboratory. At this time there is not sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available. -

Oct 23, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a postnatal sample sent for Noonan syndrome testing in published literature; clinical information was not provided (Leach et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30050098, 29907801, 20648242, 29493581, 17143282, 21387466, 12628188) -

Noonan syndrome 4

Uncertain:1

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromatosis, gingival, 1

Uncertain:1

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Uncertain:1

Jul 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 280820). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 29907801). This variant is present in population databases (rs730880218, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 451 of the SOS1 protein (p.Thr451Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.92

P;P;.

Vest4

0.77

MutPred

0.61

Loss of catalytic residue at M446 (P = 0.0342);Loss of catalytic residue at M446 (P = 0.0342);Loss of catalytic residue at M446 (P = 0.0342);

MVP

0.69

MPC

1.1

ClinPred

0.38

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.80

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