2-38996981-A-G

Position:

• chr2-38996981-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000402219.8(SOS1):​c.3022T>C​(p.Tyr1008His) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 ENST00000402219.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-38996981-A-G is Pathogenic according to our data. Variant chr2-38996981-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32270637). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.3022T>C	p.Tyr1008His	missense_variant	19/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.3022T>C	p.Tyr1008His	missense_variant	19/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.28
MutPred		0.24		Loss of phosphorylation at Y1008 (P = 0.0405);Loss of phosphorylation at Y1008 (P = 0.0405);Loss of phosphorylation at Y1008 (P = 0.0405);
MVP		0.32
MPC		0.13
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.64

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

Other links and lift over

dbSNP: rs397517163; hg19: chr2-39224122;