Genetic Variant SOS1:p.Thr378Ala (chr2-39024080-T-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_005633.4(SOS1):c.1132A>G(p.Thr378Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T378T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.57

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-39024080-T-C is Pathogenic according to our data. Variant chr2-39024080-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3614934). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005633.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOS1	NM_005633.4	MANE Select	c.1132A>G	p.Thr378Ala	missense	Exon 9 of 23	NP_005624.2
SOS1	NM_001382394.1		c.1111A>G	p.Thr371Ala	missense	Exon 9 of 23	NP_001369323.1
SOS1	NM_001382395.1		c.1132A>G	p.Thr378Ala	missense	Exon 9 of 22	NP_001369324.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOS1	ENST00000402219.8	TSL:1 MANE Select	c.1132A>G	p.Thr378Ala	missense	Exon 9 of 23	ENSP00000384675.2
SOS1	ENST00000395038.6	TSL:5	c.1132A>G	p.Thr378Ala	missense	Exon 9 of 22	ENSP00000378479.2
SOS1	ENST00000913801.1		c.1132A>G	p.Thr378Ala	missense	Exon 9 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000151

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome 4 (2)

Cardiovascular phenotype (1)

Noonan syndrome (1)

not provided (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.019

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.4

PhyloP100

7.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.12

REVEL

Benign

0.25

Sift

Benign

0.43

Sift4G

Benign

0.070

Polyphen

0.15

Vest4

0.55

MutPred

0.46

Loss of methylation at K374 (P = 0.0671)

MVP

0.77

MPC

0.81

ClinPred

0.56

GERP RS

5.9

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.46

gMVP

0.51

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over