Genetic Variant SH2D4A:p.Ile188Val (chr8-19357251-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022071.4(SH2D4A):c.562A>G(p.Ile188Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

SH2D4A
NM_022071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.16

Variant links:

Genes affected

SH2D4A (HGNC:26102): (SH2 domain containing 4A) Enables phosphatase binding activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

SH2D4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03725609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4A	NM_022071.4 link	c.562A>G	p.Ile188Val	missense_variant	Exon 5 of 10	ENST00000265807.8	NP_071354.2	Q9H788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH2D4A	ENST00000265807.8 link	c.562A>G	p.Ile188Val	missense_variant	Exon 5 of 10	2	NM_022071.4	ENSP00000265807.3	Q9H788-1
SH2D4A	ENST00000519207.5 link	c.562A>G	p.Ile188Val	missense_variant	Exon 5 of 10	1		ENSP00000428684.1	Q9H788-1
SH2D4A	ENST00000518040.5 link	c.427A>G	p.Ile143Val	missense_variant	Exon 4 of 9	2		ENSP00000429482.1	Q9H788-2
SH2D4A	ENST00000523736.1 link	c.472-3952A>G		intron_variant	Intron 3 of 3	4		ENSP00000428048.1	H0YAT1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251230

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000597

AC:

873

AN:

1461676

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

424

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000752

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000296

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000584

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562A>G (p.I188V) alteration is located in exon 5 (coding exon 4) of the SH2D4A gene. This alteration results from a A to G substitution at nucleotide position 562, causing the isoleucine (I) at amino acid position 188 to be replaced by a valine (V). 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

Benign

0.073

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.025

T;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.59

.;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.81

L;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.33

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.15

MVP

0.56

MPC

0.0059

ClinPred

0.0090

GERP RS

0.19

Varity_R

0.039

gMVP

0.036

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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