2-39023118-A-T

Position:

• chr2-39023118-A-T

Variant summary

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

The NM_005633.4(SOS1):​c.1310T>A​(p.Ile437Asn) 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. I437T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.19

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 (HGNC:):

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 chr2-39023118-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 2-39023118-A-T is Pathogenic according to our data. Variant chr2-39023118-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1310T>A	p.Ile437Asn	missense_variant	10/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1310T>A	p.Ile437Asn	missense_variant	10/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The p.I437N variant (also known as c.1310T>A), located in coding exon 10 of the SOS1 gene, results from a T to A substitution at nucleotide position 1310. The isoleucine at codon 437 is replaced by asparagine, an amino acid with dissimilar properties, and is located in the pleckstrin homology domain. This alteration has been reported in two individuals with Noonan syndrome, including as a de novo occurrence in one case (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14). Another alteration at the same codon, p.I437T (c.1310T>C), has been detected in several unrelated individuals reported to have Noonan syndrome, including de novo occurrences in affected index cases (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Moniez S et al. Eur J Endocrinol, 2018 Dec;179:409-418; Prasad RM et al. Pediatr Blood Cancer, 2018 11;65:e27362; Yang L et al. BMC Med Genet, 2018 12;19:212; Ferriero K et al. Front Pediatr, 2020 Sep;8:515; Lazzaro G et al. Mol Genet Genomic Med, 2020 04;8:e1069). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 22, 2020

This variant has been observed in individual(s) with Noonan syndrome (PMID: 24451042). This sequence change replaces isoleucine with asparagine at codon 437 of the SOS1 protein (p.Ile437Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. This variant disrupts the p.Ile437 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21387466, 24451042, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.99
MutPred		0.69		Gain of disorder (P = 0.0149);Gain of disorder (P = 0.0149);Gain of disorder (P = 0.0149);
MVP		0.93
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-39250259;