8-19319638-A-G

Variant names:

• chr8-19319638-A-G
• rs2052152535
• NM_022071.4:c.91A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022071.4(SH2D4A):​c.91A>G​(p.Met31Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,422 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SH2D4A NM_022071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4A	NM_022071.4	c.91A>G	p.Met31Val	missense_variant	Exon 2 of 10	ENST00000265807.8	NP_071354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D4A	ENST00000265807.8	c.91A>G	p.Met31Val	missense_variant	Exon 2 of 10	2	NM_022071.4	ENSP00000265807.3
SH2D4A	ENST00000519207.5	c.91A>G	p.Met31Val	missense_variant	Exon 2 of 10	1		ENSP00000428684.1
SH2D4A	ENST00000523736.1	c.49A>G	p.Met17Val	missense_variant	Exon 1 of 4	4		ENSP00000428048.1
SH2D4A	ENST00000518040.5	c.46+5815A>G		intron_variant	Intron 1 of 8	2		ENSP00000429482.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459422 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91A>G (p.M31V) alteration is located in exon 2 (coding exon 1) of the SH2D4A gene. This alteration results from a A to G substitution at nucleotide position 91, causing the methionine (M) at amino acid position 31 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.32		Gain of methylation at K30 (P = 0.0419);Gain of methylation at K30 (P = 0.0419);.;
MVP		0.47
MPC		0.026
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.50
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2052152535; hg19: chr8-19177149;