10-80603649-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001388272.1(SH2D4B):c.714C>A(p.His238Gln) 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 1,452,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 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: SH2D4B NM_001388272.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.702

Genes affected

SH2D4B (HGNC:31440): (SH2 domain containing 4B) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.12611315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D4B	NM_001388272.1	c.714C>A	p.His238Gln	missense_variant	5/8	ENST00000646907.2
SH2D4B	NM_207372.2	c.714C>A	p.His238Gln	missense_variant	5/7
SH2D4B	NM_001145719.1	c.567C>A	p.His189Gln	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D4B	ENST00000646907.2	c.714C>A	p.His238Gln	missense_variant	5/8		NM_001388272.1	P1
SH2D4B	ENST00000339284.6	c.714C>A	p.His238Gln	missense_variant	5/7	2
SH2D4B	ENST00000313455.5	c.567C>A	p.His189Gln	missense_variant	5/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000434 AC: 1 AN: 230298 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000590

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452096 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 721422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.714C>A (p.H238Q) alteration is located in exon 5 (coding exon 5) of the SH2D4B gene. This alteration results from a C to A substitution at nucleotide position 714, causing the histidine (H) at amino acid position 238 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.89	N;.;N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.011	D;.;D
Polyphen		0.0010	B;.;B
Vest4		0.21
MutPred		0.35		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.27
MPC		0.15
ClinPred		0.60	D
GERP RS		1.9
gMVP		0.35

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

Other links and lift over

dbSNP: rs1913762; hg19: chr10-82363405;