Variant 19-6754390-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005490.3(SH2D3A):c.1133T>C(p.Val378Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,534,380 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 5 hom. )

Consequence

SH2D3A
NM_005490.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.41

Variant links:

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]

SH2D3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20481497).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D3A	NM_005490.3 link	c.1133T>C	p.Val378Ala	missense_variant	7/10	ENST00000245908.11	NP_005481.2	Q9BRG2-1A8K2M8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SH2D3A	ENST00000245908.11 link	c.1133T>C	p.Val378Ala	missense_variant	7/10	1	NM_005490.3	ENSP00000245908.5	Q9BRG2-1
SH2D3A	ENST00000437152.7 link	c.767T>C	p.Val256Ala	missense_variant	6/8	2		ENSP00000393303.2	Q9BRG2-2
SH2D3A	ENST00000595681.5 link	n.1440T>C		non_coding_transcript_exon_variant	6/8	5
SH2D3A	ENST00000597168.1 link	n.443+310T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

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

GnomAD3 exomes

AF:

0.000137

AC:

AN:

160586

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

88878

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000321

Gnomad SAS exome

AF:

0.0000554

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000995

GnomAD4 exome

AF:

0.000113

AC:

156

AN:

1382354

Hom.:

Cov.:

AF XY:

0.0000923

AC XY:

AN XY:

682578

show subpopulations

Gnomad4 AFR exome

AF:

0.000634

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000383

Gnomad4 SAS exome

AF:

0.0000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000831

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.000480

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000307

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.000104

AC:

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.1133T>C (p.V378A) alteration is located in exon 7 (coding exon 6) of the SH2D3A gene. This alteration results from a T to C substitution at nucleotide position 1133, causing the valine (V) at amino acid position 378 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.65

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

.;D

Vest4

0.58

MutPred

0.59

.;Gain of disorder (P = 0.0151);

MVP

0.71

MPC

0.95

ClinPred

0.19

GERP RS

4.4

Varity_R

0.43

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over