NM_002116.8:c.261G>C

Variant names:

• chr6-29942944-G-C
• rs199474424
• NM_002116.8:c.261G>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.261G>C​(p.Glu87Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E87N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.066 (132 hom., cov: 11)
  • Exomes 𝑓: 0.12 (16383 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813

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=0.0017453134).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.261G>C	p.Glu87Asp	missense_variant	Exon 2 of 8	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.813+1837C>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.261G>C	p.Glu87Asp	missense_variant	Exon 2 of 8	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 5017 AN: 76066 Hom.: 132 Cov.: 11

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00607

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0743

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0661

GnomAD3 exomes AF: 0.154 AC: 36650 AN: 237370 Hom.: 2738 AF XY: 0.154 AC XY: 19868 AN XY: 128650

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.142

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.122 AC: 144054 AN: 1177570 Hom.: 16383 Cov.: 30 AF XY: 0.125 AC XY: 73315 AN XY: 584450

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.0998

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.0660 AC: 5023 AN: 76118 Hom.: 132 Cov.: 11 AF XY: 0.0640 AC XY: 2369 AN XY: 37026

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0866

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0425

Gnomad4 SAS AF: 0.0839

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0651

Alfa AF: 0.0297 Hom.: 59

ESP6500AA AF: 0.0368 AC: 162

ESP6500EA AF: 0.00874 AC: 75

ExAC AF: 0.154 AC: 18721

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.10	T;T;T;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.014	.;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N;N;N;.
REVEL	Benign	0.040
Sift	Uncertain	0.0070	D;D;D;.;.
Sift4G	Uncertain	0.010	D;D;D;D;.
Polyphen		0.0040	B;P;B;P;.
Vest4		0.072
MutPred		0.40		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MPC		0.081
ClinPred		0.036	T
GERP RS		0.50
Varity_R		0.54
gMVP		0.23

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: rs199474424; hg19: chr6-29910721; COSMIC: COSV65139183;