Genetic Variant SH2D4A:p.Val311Met (chr8-19373543-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022071.4(SH2D4A):c.931G>A(p.Val311Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,996 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: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SH2D4A
NM_022071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.335

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08696154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4A	NM_022071.4 link	c.931G>A	p.Val311Met	missense_variant	Exon 8 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.931G>A	p.Val311Met	missense_variant	Exon 8 of 10	2	NM_022071.4	ENSP00000265807.3	Q9H788-1
SH2D4A	ENST00000519207.5 link	c.931G>A	p.Val311Met	missense_variant	Exon 8 of 10	1		ENSP00000428684.1	Q9H788-1
SH2D4A	ENST00000518040.5 link	c.796G>A	p.Val266Met	missense_variant	Exon 7 of 9	2		ENSP00000429482.1	Q9H788-2
SH2D4A	ENST00000522328.1 link	n.488G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453996

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723356

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000456

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000577

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

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.931G>A (p.V311M) alteration is located in exon 8 (coding exon 7) of the SH2D4A gene. This alteration results from a G to A substitution at nucleotide position 931, causing the valine (V) at amino acid position 311 to be replaced by a methionine (M). 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

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.3

DANN

Benign

0.93

DEOGEN2

Benign

0.049

T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.20

.;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.087

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

N;.;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.16

N;N;N

REVEL

Benign

0.011

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.21

MutPred

0.28

Gain of MoRF binding (P = 0.0946);.;Gain of MoRF binding (P = 0.0946);

MVP

0.13

MPC

0.0056

ClinPred

0.046

GERP RS

-0.85

Varity_R

0.034

gMVP

0.30

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

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