6-31356754-C-T

Position:

• chr6-31356754-C-T

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.277G>A​(p.Ala93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A93R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (5437 hom., cov: 5)
  • Exomes 𝑓: 0.66 (264581 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.32

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=2.3709429E-6).
• BP6: Variant 6-31356754-C-T is Benign according to our data. Variant chr6-31356754-C-T is described in ClinVar as [Benign]. Clinvar id is 3061033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-B	NM_005514.8	c.277G>A	p.Ala93Thr	missense_variant	2/8	ENST00000412585.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-B	ENST00000412585.7	c.277G>A	p.Ala93Thr	missense_variant	2/8		NM_005514.8	P1
	ENST00000603274.1	n.108C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 15957 AN: 36896 Hom.: 5432 Cov.: 5

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.733

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.471

GnomAD3 exomes AF: 0.766 AC: 149551 AN: 195270 Hom.: 64720 AF XY: 0.768 AC XY: 82003 AN XY: 106720

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.874

Gnomad EAS exome AF: 0.720

Gnomad SAS exome AF: 0.819

Gnomad FIN exome AF: 0.738

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.766

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.662 AC: 600088 AN: 907044 Hom.: 264581 Cov.: 18 AF XY: 0.666 AC XY: 300379 AN XY: 450786

Gnomad4 AFR exome AF: 0.512

Gnomad4 AMR exome AF: 0.858

Gnomad4 ASJ exome AF: 0.873

Gnomad4 EAS exome AF: 0.635

Gnomad4 SAS exome AF: 0.785

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.645

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.433 AC: 15979 AN: 36942 Hom.: 5437 Cov.: 5 AF XY: 0.426 AC XY: 7462 AN XY: 17512

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.825

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.470

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.467

Alfa AF: 0.641 Hom.: 3628

ESP6500AA AF: 0.632 AC: 2616

ESP6500EA AF: 0.656 AC: 5337

ExAC AF: 0.694 AC: 82387

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HLA-B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as 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	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.84
DEOGEN2	Benign	0.020	T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.045	T;T;T
MetaRNN	Benign	0.0000024	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-0.44	N;.;N
REVEL	Benign	0.29
Sift	Benign	0.52	T;.;T
Sift4G	Benign	0.37	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.047
MPC		0.22
ClinPred		0.00033	T
GERP RS		-2.7
Varity_R		0.066
gMVP		0.047

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: rs1131204; hg19: chr6-31324531; COSMIC: COSV69520472; COSMIC: COSV69520472;