19-6760963-T-C

Position:

• chr19-6760963-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005490.3(SH2D3A):​c.94A>G​(p.Asn32Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,611,446 control chromosomes in the GnomAD database, including 44,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6235 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38535 hom.)
• Consequence: SH2D3A NM_005490.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.379

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007875234).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D3A	NM_005490.3	c.94A>G	p.Asn32Asp	missense_variant	3/10	ENST00000245908.11	NP_005481.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D3A	ENST00000245908.11	c.94A>G	p.Asn32Asp	missense_variant	3/10	1	NM_005490.3	ENSP00000245908	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40723 AN: 152038 Hom.: 6223 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.243

GnomAD3 exomes AF: 0.218 AC: 53189 AN: 244140 Hom.: 6647 AF XY: 0.221 AC XY: 29367 AN XY: 132832

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.0649

Gnomad SAS exome AF: 0.298

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.223 AC: 326135 AN: 1459290 Hom.: 38535 Cov.: 33 AF XY: 0.225 AC XY: 163610 AN XY: 725710

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.0668

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.268 AC: 40774 AN: 152156 Hom.: 6235 Cov.: 32 AF XY: 0.263 AC XY: 19532 AN XY: 74384

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.0601

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.246

Alfa AF: 0.224 Hom.: 10434

Bravo AF: 0.270

TwinsUK AF: 0.234 AC: 868

ALSPAC AF: 0.214 AC: 824

ESP6500AA AF: 0.416 AC: 1830

ESP6500EA AF: 0.216 AC: 1858

ExAC AF: 0.227 AC: 27542

Asia WGS AF: 0.179 AC: 622 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.69
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.041
MPC		0.29
ClinPred		0.00069	T
GERP RS		3.7
Varity_R		0.053
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7258236; hg19: chr19-6760974; COSMIC: COSV55586457;