chr2-39051262-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_005633.4(SOS1):c.746T>C(p.Ile249Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.20

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
fibromatosis, gingival, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary gingival fibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_005633.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.746T>C	p.Ile249Thr	missense_variant	Exon 6 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.746T>C	p.Ile249Thr	missense_variant	Exon 6 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251256

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000137

AC:

AN:

1459024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109540

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I249T variant (also known as c.746T>C), located in coding exon 6 of the SOS1 gene, results from a T to C substitution at nucleotide position 746. The isoleucine at codon 249 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RASopathy

Uncertain:1

Aug 22, 2022

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) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 543967). This missense change has been observed in individual(s) with clinical features of SOS1-related conditions (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 249 of the SOS1 protein (p.Ile249Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

M;M;.

PhyloP100

9.2

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.81

Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);

MVP

0.99

MPC

1.7

ClinPred

0.98

GERP RS

5.7

Varity_R

0.80

gMVP

0.77

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over