19-6752634-C-T

Variant names:

• chr19-6752634-C-T
• rs777157553
• NM_005490.3:c.1690G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005490.3(SH2D3A):​c.1690G>A​(p.Val564Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 1,556,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. V564L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10693547).

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.1690G>A	p.Val564Ile	missense	Exon 10 of 10	NP_005481.2	Q9BRG2-1
	SH2D3A	NM_001439225.1		c.1777G>A	p.Val593Ile	missense	Exon 9 of 9	NP_001426154.1
	SH2D3A	NM_001386585.1		c.1687G>A	p.Val563Ile	missense	Exon 10 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.1690G>A	p.Val564Ile	missense	Exon 10 of 10	ENSP00000245908.5	Q9BRG2-1
	SH2D3A	ENST00000892014.1		c.1777G>A	p.Val593Ile	missense	Exon 9 of 9	ENSP00000562073.1
	SH2D3A	ENST00000892016.1		c.1774G>A	p.Val592Ile	missense	Exon 9 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166748 AF XY: 0.0000112

Gnomad AFR exome AF: 0.000107

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1404734 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692636

African (AFR) AF: 0.00 AC: 0 AN: 32168

American (AMR) AF: 0.00 AC: 0 AN: 36786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 36746

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79980

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081604

Other (OTH) AF: 0.00 AC: 0 AN: 58110

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.2
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.061
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.028
Sift	Benign	0.43	T
Sift4G	Benign	0.43	T
Polyphen		0.56	P
Vest4		0.13
MVP		0.48
MPC		1.2
ClinPred		0.12	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.15
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777157553; hg19: chr19-6752645;