2-39014838-A-T

Position:

• chr2-39014838-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000402219.8(SOS1):​c.1867T>A​(p.Phe623Ile) 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F623E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 ENST00000402219.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.92

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39014838-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179739.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 2-39014838-A-T is Pathogenic according to our data. Variant chr2-39014838-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636262.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39014838-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1867T>A	p.Phe623Ile	missense_variant	11/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1867T>A	p.Phe623Ile	missense_variant	11/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome and Noonan-related syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Feb 28, 2019	The c.1867T>A (p.Phe623Ile) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of Noonan syndrome (PS2; PMID 17586837, 20673819). The p.Phe623Ile variant has also been identified in another independent occurrence in a patient with clinical features of Noonan syndrome (PS4_Supporting; PMID 20673819). This variant was absent from large population studies (PM2; gnomAD; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Phe623Ile variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, two different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Glu) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM2, PP2, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 13, 2020	- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Apr 12, 2023

PS2, PS4_Moderate, PM2, PP2, PP3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 29493581, 17586837, 20673819) -

Fibromatosis, gingival, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 28, 2020

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS2_Mod,PS4_Mod,PM2,PP2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.85		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.94

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: rs727505093; hg19: chr2-39241979;