6-31356870-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005514.8(HLA-B):c.161A>G(p.Asp54Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,141,880 control chromosomes in the GnomAD database, including 8,691 homozygotes. 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 Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 9)
  • Exomes 𝑓: 0.041 (8684 hom.)
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.711

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00765267).
• BP6: Variant 6-31356870-T-C is Benign according to our data. Variant chr6-31356870-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.161A>G	p.Asp54Gly	missense_variant	2/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.161A>G	p.Asp54Gly	missense_variant	2/8		NM_005514.8	P1
	ENST00000603274.1	n.224T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 415 AN: 68934 Hom.: 7 Cov.: 9

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00613

Gnomad ASJ AF: 0.00370

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00646

Gnomad MID AF: 0.00667

Gnomad NFE AF: 0.00829

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.0360 AC: 8412 AN: 233410 Hom.: 801 AF XY: 0.0370 AC XY: 4698 AN XY: 126874

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0304

Gnomad EAS exome AF: 0.00287

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.0511

Gnomad NFE exome AF: 0.0466

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0413 AC: 44337 AN: 1072868 Hom.: 8684 Cov.: 24 AF XY: 0.0412 AC XY: 22045 AN XY: 534530

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.0347

Gnomad4 ASJ exome AF: 0.0270

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.00603 AC: 416 AN: 69012 Hom.: 7 Cov.: 9 AF XY: 0.00610 AC XY: 198 AN XY: 32468

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00612

Gnomad4 ASJ AF: 0.00370

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00226

Gnomad4 FIN AF: 0.00646

Gnomad4 NFE AF: 0.00832

Gnomad4 OTH AF: 0.00234

Alfa AF: 0.0418 Hom.: 58

ESP6500AA AF: 0.0332 AC: 143

ESP6500EA AF: 0.0493 AC: 410

ExAC AF: 0.0466 AC: 5558

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.44
DEOGEN2	Benign	0.027	T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.029	D;.;D
Polyphen		0.0010	B;.;.
Vest4		0.096
MPC		0.96
ClinPred		0.10	T
GERP RS		2.0
Varity_R		0.50
gMVP		0.36

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: rs9266183; hg19: chr6-31324647;