6-29942965-G-C

Variant names:

• chr6-29942965-G-C
• rs78306866
• NM_002116.8:c.282G>C

Variant summary

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

The NM_002116.8(HLA-A):​c.282G>C​(p.Gln94His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.41 (6970 hom., cov: 8)
  • Exomes 𝑓: 0.60 (232696 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A 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 so that they can be recognized by cytotoxic T cells. 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, exons 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. More than 6000 HLA-A alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

ENSG00000227766 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1530621E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.282G>C	p.Gln94His	missense_variant	Exon 2 of 8	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.813+1816C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.282G>C	p.Gln94His	missense_variant	Exon 2 of 8	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.413 AC: 25136 AN: 60800 Hom.: 6946 Cov.: 8

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.463

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.701 AC: 166986 AN: 238122 Hom.: 59063 AF XY: 0.698 AC XY: 90221 AN XY: 129246

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.727

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.678

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.687

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.599 AC: 586495 AN: 978738 Hom.: 232696 Cov.: 26 AF XY: 0.599 AC XY: 293013 AN XY: 489330

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.587

Gnomad4 SAS exome AF: 0.639

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.414 AC: 25198 AN: 60868 Hom.: 6970 Cov.: 8 AF XY: 0.404 AC XY: 11904 AN XY: 29498

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.425

Alfa AF: 0.659 Hom.: 5772

ESP6500AA AF: 0.605 AC: 2661

ESP6500EA AF: 0.655 AC: 5625

ExAC AF: 0.654 AC: 79293

Asia WGS AF: 0.673 AC: 2338 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.39
DEOGEN2	Benign	0.021	T;T;T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.0088	.;T;T;T;T
MetaRNN	Benign	0.000012	T;T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.30	N;N;N;N;.
REVEL	Benign	0.044
Sift	Benign	1.0	T;T;T;.;.
Sift4G	Benign	0.67	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.10
MutPred		0.11		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MPC		0.078
ClinPred		0.0021	T
GERP RS		-0.59
Varity_R		0.23
gMVP		0.13

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: rs78306866; hg19: chr6-29910742; COSMIC: COSV65140297;