chr19-6754094-G-A

Variant names:

• chr19-6754094-G-A
• rs747134741
• NM_005490.3:c.1342C>T

Variant summary

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

The NM_005490.3(SH2D3A):​c.1342C>T​(p.Gln448*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH2D3A NM_005490.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71
• 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: 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.1342C>T	p.Gln448*	stop_gained	Exon 8 of 10	NP_005481.2	Q9BRG2-1
	SH2D3A	NM_001439225.1		c.1429C>T	p.Gln477*	stop_gained	Exon 7 of 9	NP_001426154.1
	SH2D3A	NM_001386585.1		c.1339C>T	p.Gln447*	stop_gained	Exon 8 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.1342C>T	p.Gln448*	stop_gained	Exon 8 of 10	ENSP00000245908.5	Q9BRG2-1
	SH2D3A	ENST00000892014.1		c.1429C>T	p.Gln477*	stop_gained	Exon 7 of 9	ENSP00000562073.1
	SH2D3A	ENST00000892016.1		c.1426C>T	p.Gln476*	stop_gained	Exon 7 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460704 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726616

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111512

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		3.7
Vest4		0.081
GERP RS		2.3
Mutation Taster		=45/155	disease causing (fs/PTC)

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: rs747134741; hg19: chr19-6754105;