2-39058765-A-T

Variant names:

• chr2-39058765-A-T
• rs730881054
• NM_005633.4:c.253T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005633.4(SOS1):​c.253T>A​(p.Trp85Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 2-39058765-A-T is Pathogenic according to our data. Variant chr2-39058765-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 40647.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.253T>A	p.Trp85Arg	missense_variant	Exon 3 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.253T>A	p.Trp85Arg	missense_variant	Exon 3 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 28, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W85R mutation has not been previously reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The W85R mutation is considered to be a non-conservative amino acid substitution as a neutral, non-polar residue (Trp) is replaced by a positively charged, polar residue (Arg). The position in the protein at which this substitution occurs is highly conserved across species, but not in related proteins. While there have been no disease-causing mutations reported in the SOS1 gene prior to codon Proline 102, in vitro functional studies indicate that the Trp85 codon is a component of the inhibitory histone domain interface and that when mutated can lead to the partial activation of SOS1 (Gureasko et al., 2009). Additionally, another nucleotide change (c.253 T>C) resulting in this same missense change has been observed de novo in a patient tested at GeneDx. Therefore, W85R is interpreted to be a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-12	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.89
MutPred		0.47		Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);.;
MVP		0.91
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs730881054; hg19: chr2-39285906;