19-6754274-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005490.3(SH2D3A):​c.1249A>T​(p.Met417Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,352 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M417V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1249A>T	p.Met417Leu	missense	Exon 7 of 10	NP_005481.2	Q9BRG2-1
	SH2D3A	NM_001439225.1		c.1249A>T	p.Met417Leu	missense	Exon 7 of 9	NP_001426154.1
	SH2D3A	NM_001386585.1		c.1246A>T	p.Met416Leu	missense	Exon 7 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.1249A>T	p.Met417Leu	missense	Exon 7 of 10	ENSP00000245908.5	Q9BRG2-1
	SH2D3A	ENST00000892014.1		c.1249A>T	p.Met417Leu	missense	Exon 7 of 9	ENSP00000562073.1
	SH2D3A	ENST00000892016.1		c.1246A>T	p.Met416Leu	missense	Exon 7 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441352 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 716752

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 43790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 84928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108068

Other (OTH) AF: 0.00 AC: 0 AN: 59806

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.62
MutPred		0.60		Gain of helix (P = 0.0696)
MVP		0.57
MPC		0.79
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.80
Mutation Taster		=70/30	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

dbSNP: rs1316012391; hg19: chr19-6754285;