14-50118387-A-G

Position:

• chr14-50118387-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006939.4(SOS2):​c.3956T>C​(p.Leu1319Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14805123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3956T>C	p.Leu1319Ser	missense_variant	23/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3956T>C	p.Leu1319Ser	missense_variant	23/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3857T>C	p.Leu1286Ser	missense_variant	22/22	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The p.L1319S variant (also known as c.3956T>C), located in coding exon 23 of the SOS2 gene, results from a T to C substitution at nucleotide position 3956. The leucine at codon 1319 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.22
Sift	Benign	0.075	T;T
Sift4G	Benign	0.080	T;T
Polyphen		0.023	B;.
Vest4		0.064
MutPred		0.18		Gain of phosphorylation at L1319 (P = 0.0163);.;
MVP		0.22
MPC		0.27
ClinPred		0.40	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.035
gMVP		0.38

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: chr14-50585105;