rs2308466

chr6-31356226-T-Achr6-31356226-T-Cchr6-31356226-T-G

Variant summary

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

The NM_005514.8(HLA-B):c.560A>T(p.Glu187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 31,466 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. E187L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (460 hom., cov: 4)
  • Exomes 𝑓: 0.23 (16763 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.96

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052467883).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.560A>T	p.Glu187Val	missense_variant	3/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.560A>T	p.Glu187Val	missense_variant	3/8		NM_005514.8	P1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 3500 AN: 31468 Hom.: 460 Cov.: 4

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0436

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.219

GnomAD3 exomes AF: 0.381 AC: 64927 AN: 170240 Hom.: 6716 AF XY: 0.381 AC XY: 35450 AN XY: 92970

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.480

Gnomad SAS exome AF: 0.404

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.384

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.231 AC: 209131 AN: 905958 Hom.: 16763 Cov.: 17 AF XY: 0.232 AC XY: 106037 AN XY: 456104

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.111 AC: 3501 AN: 31466 Hom.: 460 Cov.: 4 AF XY: 0.108 AC XY: 1594 AN XY: 14806

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0436

Gnomad4 NFE AF: 0.0777

Gnomad4 OTH AF: 0.216

Alfa AF: 0.307 Hom.: 515

ESP6500AA AF: 0.542 AC: 2317

ESP6500EA AF: 0.464 AC: 3870

ExAC AF: 0.381 AC: 45558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.076
Dann	Benign	0.47
DEOGEN2	Benign	0.026	T;.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.0019	T;T;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.055	T;.;T
Sift4G	Benign	0.19	T;.;T
Polyphen		0.019	B;.;.
Vest4		0.042
MPC		0.27
ClinPred		0.028	T
GERP RS		-6.4
Varity_R		0.57
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2308466; hg19: chr6-31324003; COSMIC: COSV69520675; COSMIC: COSV69520675;