10-80603625-G-C

Variant names:

• chr10-80603625-G-C
• rs148470229
• NM_001388272.1:c.690G>C

Variant summary

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

The NM_001388272.1(SH2D4B):​c.690G>C​(p.Gln230His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,254 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH2D4B NM_001388272.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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=0.25772417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D4B	NM_001388272.1	c.690G>C	p.Gln230His	missense_variant	Exon 5 of 8	ENST00000646907.2	NP_001375201.1
SH2D4B	NM_207372.2	c.690G>C	p.Gln230His	missense_variant	Exon 5 of 7		NP_997255.2
SH2D4B	NM_001145719.1	c.543G>C	p.Gln181His	missense_variant	Exon 5 of 7		NP_001139191.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D4B	ENST00000646907.2	c.690G>C	p.Gln230His	missense_variant	Exon 5 of 8		NM_001388272.1	ENSP00000494732.1
SH2D4B	ENST00000339284.6	c.690G>C	p.Gln230His	missense_variant	Exon 5 of 7	2		ENSP00000345295.2
SH2D4B	ENST00000313455.5	c.543G>C	p.Gln181His	missense_variant	Exon 5 of 7	2		ENSP00000314242.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436254 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 711994

Gnomad4 AFR exome AF: 0.0000302

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.690G>C (p.Q230H) alteration is located in exon 5 (coding exon 5) of the SH2D4B gene. This alteration results from a G to C substitution at nucleotide position 690, causing the glutamine (Q) at amino acid position 230 to be replaced by a histidine (H). 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	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.089
Sift	Uncertain	0.011	D;.;D
Sift4G	Uncertain	0.016	D;.;D
Polyphen		0.96	D;.;D
Vest4		0.36
MutPred		0.22		Gain of methylation at R228 (P = 0.1297);Gain of methylation at R228 (P = 0.1297);.;
MVP		0.69
MPC		0.15
ClinPred		0.69	D
GERP RS		4.2
gMVP		0.18

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: rs148470229; hg19: chr10-82363381;