8-19334705-T-G

Variant names:

• chr8-19334705-T-G
• NM_022071.4:c.361T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022071.4(SH2D4A):​c.361T>G​(p.Phe121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.9e-7 (0 hom.)
• Consequence: SH2D4A NM_022071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.216

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 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=0.051775962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4A	NM_022071.4	c.361T>G	p.Phe121Val	missense_variant	Exon 4 of 10	ENST00000265807.8	NP_071354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D4A	ENST00000265807.8	c.361T>G	p.Phe121Val	missense_variant	Exon 4 of 10	2	NM_022071.4	ENSP00000265807.3
SH2D4A	ENST00000519207.5	c.361T>G	p.Phe121Val	missense_variant	Exon 4 of 10	1		ENSP00000428684.1
SH2D4A	ENST00000518040.5	c.226T>G	p.Phe76Val	missense_variant	Exon 3 of 9	2		ENSP00000429482.1
SH2D4A	ENST00000523736.1	c.319T>G	p.Phe107Val	missense_variant	Exon 3 of 4	4		ENSP00000428048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451108 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721480

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361T>G (p.F121V) alteration is located in exon 4 (coding exon 3) of the SH2D4A gene. This alteration results from a T to G substitution at nucleotide position 361, causing the phenylalanine (F) at amino acid position 121 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	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.6
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T;.;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.52	.;T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;.;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.2	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.029	B;.;B;.
Vest4		0.40
MutPred		0.24		Gain of methylation at K126 (P = 0.193);.;Gain of methylation at K126 (P = 0.193);.;
MVP		0.23
MPC		0.0051
ClinPred		0.062	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.061

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-19192216;