19-6754274-T-C

Variant names:

• chr19-6754274-T-C
• rs1316012391
• NM_005490.3:c.1249A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005490.3(SH2D3A):​c.1249A>G​(p.Met417Val) 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

Genes affected

SH2D3A (HGNC:16885): (SH2 domain containing 3A) Predicted to enable guanyl-nucleotide exchange factor activity and phosphotyrosine residue binding activity. Predicted to be involved in positive regulation of peptidyl-serine phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D3A	NM_005490.3	c.1249A>G	p.Met417Val	missense_variant	Exon 7 of 10	ENST00000245908.11	NP_005481.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D3A	ENST00000245908.11	c.1249A>G	p.Met417Val	missense_variant	Exon 7 of 10	1	NM_005490.3	ENSP00000245908.5
SH2D3A	ENST00000437152.7	c.883A>G	p.Met295Val	missense_variant	Exon 6 of 8	2		ENSP00000393303.2
SH2D3A	ENST00000595681.5	n.1556A>G		non_coding_transcript_exon_variant	Exon 6 of 8	5
SH2D3A	ENST00000597168.1	n.443+426A>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441352 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 716752

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1249A>G (p.M417V) alteration is located in exon 7 (coding exon 6) of the SH2D3A gene. This alteration results from a A to G substitution at nucleotide position 1249, causing the methionine (M) at amino acid position 417 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.55		.;Gain of helix (P = 0.0696);
MVP		0.58
MPC		0.85
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.87
gMVP		0.86

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: rs1316012391; hg19: chr19-6754285;