rs7075840

chr10-80603648-A-Gchr10-80603648-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388272.1(SH2D4B):c.713A>G(p.His238Arg) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,602,382 control chromosomes in the GnomAD database, including 62,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H238Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8445 hom., cov: 33)
  • Exomes 𝑓: 0.26 (53936 hom.)
• Consequence: SH2D4B NM_001388272.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018744469).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D4B	NM_001388272.1	c.713A>G	p.His238Arg	missense_variant	5/8	ENST00000646907.2
SH2D4B	NM_207372.2	c.713A>G	p.His238Arg	missense_variant	5/7
SH2D4B	NM_001145719.1	c.566A>G	p.His189Arg	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D4B	ENST00000646907.2	c.713A>G	p.His238Arg	missense_variant	5/8		NM_001388272.1	P1
SH2D4B	ENST00000339284.6	c.713A>G	p.His238Arg	missense_variant	5/7	2
SH2D4B	ENST00000313455.5	c.566A>G	p.His189Arg	missense_variant	5/7	2

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48666 AN: 151932 Hom.: 8426 Cov.: 33

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.297 AC: 67986 AN: 228966 Hom.: 10687 AF XY: 0.292 AC XY: 36237 AN XY: 123966

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.496

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.264 AC: 383232 AN: 1450332 Hom.: 53936 Cov.: 36 AF XY: 0.265 AC XY: 190542 AN XY: 720308

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.551

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.321 AC: 48738 AN: 152050 Hom.: 8445 Cov.: 33 AF XY: 0.321 AC XY: 23877 AN XY: 74324

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.311

Alfa AF: 0.286 Hom.: 3227

Bravo AF: 0.326

TwinsUK AF: 0.246 AC: 912

ALSPAC AF: 0.252 AC: 970

ESP6500AA AF: 0.433 AC: 1903

ESP6500EA AF: 0.257 AC: 2206

ExAC AF: 0.287 AC: 34732

Asia WGS AF: 0.394 AC: 1367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.65
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.11	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	3.9	N;.;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.055
MPC		0.18
ClinPred		0.0045	T
GERP RS		6.0
gMVP		0.34

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: rs7075840; hg19: chr10-82363404; COSMIC: COSV57893065; COSMIC: COSV57893065;