chr2-39054646-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005633.4(SOS1):c.688T>G(p.Phe230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,583,910 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. F230L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.38

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_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.688T>G	p.Phe230Val	missense_variant	Exon 5 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.688T>G	p.Phe230Val	missense_variant	Exon 5 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250966

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1431702

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

714216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32862

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

85548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1084968

Other (OTH)

AF:

0.0000168

AC:

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

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

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000353

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Apr 30, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2019

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: SOS1 c.688T>G (p.Phe230Val) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.688T>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Dec 23, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD) -

Cardiovascular phenotype

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F230V variant (also known as c.688T>G), located in coding exon 5 of the SOS1 gene, results from a T to G substitution at nucleotide position 688. The phenylalanine at codon 230 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RASopathy

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the SOS1 protein (p.Phe230Val). This variant is present in population databases (rs397517177, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 40658). Invitae Evidence 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 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;T;T

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

8.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.7

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.039

D;D;D

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.51

P;P;.

Vest4

0.58

MutPred

0.48

Loss of ubiquitination at K235 (P = 0.1151);Loss of ubiquitination at K235 (P = 0.1151);Loss of ubiquitination at K235 (P = 0.1151);

MVP

0.75

MPC

1.3

ClinPred

0.70

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.60

Mutation Taster

=26/74

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over