NM_005490.3:c.1456G>A

Variant names:

• chr19-6753570-C-T
• NM_005490.3:c.1456G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005490.3(SH2D3A):​c.1456G>A​(p.Val486Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.149
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04617375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005490.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D3A	NM_005490.3	MANE Select	c.1456G>A	p.Val486Ile	missense	Exon 9 of 10	NP_005481.2	Q9BRG2-1
	SH2D3A	NM_001439225.1		c.1543G>A	p.Val515Ile	missense	Exon 8 of 9	NP_001426154.1
	SH2D3A	NM_001386585.1		c.1453G>A	p.Val485Ile	missense	Exon 9 of 10	NP_001373514.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D3A	ENST00000245908.11	TSL:1 MANE Select	c.1456G>A	p.Val486Ile	missense	Exon 9 of 10	ENSP00000245908.5	Q9BRG2-1
	SH2D3A	ENST00000892014.1		c.1543G>A	p.Val515Ile	missense	Exon 8 of 9	ENSP00000562073.1
	SH2D3A	ENST00000892016.1		c.1540G>A	p.Val514Ile	missense	Exon 8 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428588 Hom.: 0 Cov.: 34 AF XY: 0.00000282 AC XY: 2 AN XY: 707972

African (AFR) AF: 0.00 AC: 0 AN: 32882

American (AMR) AF: 0.00 AC: 0 AN: 40118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38014

South Asian (SAS) AF: 0.0000244 AC: 2 AN: 81912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096386

Other (OTH) AF: 0.00 AC: 0 AN: 59116

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.5
DANN	Benign	0.89
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.15
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.018
Sift	Benign	0.38	T
Sift4G	Benign	0.21	T
Polyphen		0.035	B
Vest4		0.13
MutPred		0.20		Loss of sheet (P = 0.0457)
MVP		0.11
MPC		0.21
ClinPred		0.18	T
GERP RS		-2.9
Varity_R		0.029
gMVP		0.056
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr19-6753581;