chr2-39022999-G-T

Position:

• chr2-39022999-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_005633.4(SOS1):​c.1429C>A​(p.Gln477Lys) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q477R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39022998-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27048028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1429C>A	p.Gln477Lys	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1429C>A	p.Gln477Lys	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 13, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Gln477Lys v ariant in SOS1 has not been reported in the literature nor previously identified by our laboratory. However, two other changes at this position (Gln477Arg and G ln477His) have been reported in individuals with Noonan syndrome (Longoni 2012, Lepri 2011, Zenker 2007). The Gln477Arg variant was shown to occur de novo in on e proband (Longoni 2012) while the Gln477His was identified in two probands, but neither had parental testing (Lepri 2011). Another individual was shown to be a compound heterozygote (Gln477His+ Pro478Leu) with both variants in cis and occu rring de novo (Zenker 2007). Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gln477Lys variant may not impact the protein, though this information is not predictive e nough to rule out pathogenicity. Although these data suggest the Gln477Lys vari ant may be associated with disease, additional information such as segregation s tudies and functional analyses are needed to fully assess its clinical significa nce. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Benign	0.028
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.39	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.44
MutPred		0.48		Gain of ubiquitination at Q477 (P = 0.0247);Gain of ubiquitination at Q477 (P = 0.0247);Gain of ubiquitination at Q477 (P = 0.0247);
MVP		0.71
MPC		0.80
ClinPred		0.33	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.30

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: rs397517152; hg19: chr2-39250140;