8-19357257-C-A

Variant names:

• chr8-19357257-C-A
• NM_022071.4:c.568C>A

Variant summary

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

The NM_022071.4(SH2D4A):​c.568C>A​(p.Arg190Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH2D4A NM_022071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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.568C>A	p.Arg190Ser	missense_variant	Exon 5 of 10	ENST00000265807.8	NP_071354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D4A	ENST00000265807.8	c.568C>A	p.Arg190Ser	missense_variant	Exon 5 of 10	2	NM_022071.4	ENSP00000265807.3
SH2D4A	ENST00000519207.5	c.568C>A	p.Arg190Ser	missense_variant	Exon 5 of 10	1		ENSP00000428684.1
SH2D4A	ENST00000518040.5	c.433C>A	p.Arg145Ser	missense_variant	Exon 4 of 9	2		ENSP00000429482.1
SH2D4A	ENST00000523736.1	c.472-3946C>A		intron_variant	Intron 3 of 3	4		ENSP00000428048.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568C>A (p.R190S) alteration is located in exon 5 (coding exon 4) of the SH2D4A gene. This alteration results from a C to A substitution at nucleotide position 568, causing the arginine (R) at amino acid position 190 to be replaced by a serine (S). 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	0.29
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.30	T;T;T
Polyphen		0.88	P;.;P
Vest4		0.45
MutPred		0.18		Gain of ubiquitination at K192 (P = 0.0329);.;Gain of ubiquitination at K192 (P = 0.0329);
MVP		0.93
MPC		0.0065
ClinPred		0.78	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-19214768;