6-31356226-T-A

Variant names:

• chr6-31356226-T-A
• rs2308466
• NM_005514.8:c.560A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005514.8(HLA-B):​c.560A>T​(p.Glu187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 34 publications found

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]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052467883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8	c.560A>T	p.Glu187Val	missense_variant	Exon 3 of 8	ENST00000412585.7	NP_005505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7	c.560A>T	p.Glu187Val	missense_variant	Exon 3 of 8	6	NM_005514.8	ENSP00000399168.2

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

GnomAD2 exomes AF: 0.381 AC: 64927 AN: 170240 AF XY: 0.381

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 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

African (AFR) AF: 0.392 AC: 8650 AN: 22080

American (AMR) AF: 0.329 AC: 9536 AN: 28956

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 5023 AN: 15544

East Asian (EAS) AF: 0.300 AC: 7163 AN: 23890

South Asian (SAS) AF: 0.297 AC: 19480 AN: 65554

European-Finnish (FIN) AF: 0.169 AC: 4922 AN: 29100

Middle Eastern (MID) AF: 0.343 AC: 958 AN: 2796

European-Non Finnish (NFE) AF: 0.211 AC: 143905 AN: 681082

Other (OTH) AF: 0.257 AC: 9494 AN: 36956

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.177 AC: 1095 AN: 6200

American (AMR) AF: 0.168 AC: 444 AN: 2636

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 51 AN: 368

East Asian (EAS) AF: 0.152 AC: 191 AN: 1260

South Asian (SAS) AF: 0.179 AC: 145 AN: 810

European-Finnish (FIN) AF: 0.0436 AC: 103 AN: 2364

Middle Eastern (MID) AF: 0.456 AC: 31 AN: 68

European-Non Finnish (NFE) AF: 0.0777 AC: 1342 AN: 17262

Other (OTH) AF: 0.216 AC: 79 AN: 366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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
PhyloP100		-9.0
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2308466; hg19: chr6-31324003; COSMIC: COSV69520675; COSMIC: COSV69520675;