rs1059449

Variant names:

• chr6-29942921-G-A
• rs1059449
• NM_002116.8:c.238G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002116.8(HLA-A):​c.238G>A​(p.Gly80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 1,479,646 control chromosomes in the GnomAD database, including 4,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G80G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.089 (553 hom., cov: 15)
  • Exomes 𝑓: 0.052 (3740 hom.)
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023474097).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	NM_002116.8	MANE Select	c.238G>A	p.Gly80Arg	missense	Exon 2 of 8	NP_002107.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.238G>A	p.Gly80Arg	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
	HLA-A	ENST00000952344.1		c.238G>A	p.Gly80Arg	missense	Exon 2 of 8	ENSP00000622403.1
	HLA-A	ENST00000706894.1		c.238G>A	p.Gly80Arg	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 8849 AN: 99760 Hom.: 550 Cov.: 15

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00339

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0611 AC: 15280 AN: 250018 AF XY: 0.0586

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0936

Gnomad ASJ exome AF: 0.0553

Gnomad EAS exome AF: 0.0470

Gnomad FIN exome AF: 0.0397

Gnomad NFE exome AF: 0.0487

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0515 AC: 71063 AN: 1379790 Hom.: 3740 Cov.: 41 AF XY: 0.0508 AC XY: 34796 AN XY: 685360

African (AFR) AF: 0.155 AC: 4981 AN: 32054

American (AMR) AF: 0.0906 AC: 3661 AN: 40396

Ashkenazi Jewish (ASJ) AF: 0.0538 AC: 1293 AN: 24034

East Asian (EAS) AF: 0.0702 AC: 2338 AN: 33310

South Asian (SAS) AF: 0.0431 AC: 3585 AN: 83144

European-Finnish (FIN) AF: 0.0350 AC: 1625 AN: 46386

Middle Eastern (MID) AF: 0.0836 AC: 403 AN: 4822

European-Non Finnish (NFE) AF: 0.0472 AC: 49998 AN: 1059520

Other (OTH) AF: 0.0566 AC: 3179 AN: 56124

GnomAD4 genome AF: 0.0889 AC: 8874 AN: 99856 Hom.: 553 Cov.: 15 AF XY: 0.0871 AC XY: 4210 AN XY: 48350

African (AFR) AF: 0.163 AC: 4733 AN: 28956

American (AMR) AF: 0.108 AC: 932 AN: 8608

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 137 AN: 2318

East Asian (EAS) AF: 0.0502 AC: 172 AN: 3428

South Asian (SAS) AF: 0.0364 AC: 124 AN: 3410

European-Finnish (FIN) AF: 0.0289 AC: 193 AN: 6668

Middle Eastern (MID) AF: 0.100 AC: 21 AN: 210

European-Non Finnish (NFE) AF: 0.0546 AC: 2420 AN: 44322

Other (OTH) AF: 0.104 AC: 140 AN: 1346

Alfa AF: 0.0593 Hom.: 108

ESP6500AA AF: 0.138 AC: 609

ESP6500EA AF: 0.0492 AC: 423

ExAC AF: 0.0618 AC: 7505

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.0540

EpiControl AF: 0.0561

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.048
Sift	Benign	0.036	D
Sift4G	Uncertain	0.019	D
Polyphen		0.81	P
Vest4		0.11
MutPred		0.74		Gain of solvent accessibility (P = 0.0263)
MPC		0.38
ClinPred		0.093	T
GERP RS		2.8
PromoterAI		0.037	Neutral
Varity_R		0.37
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1059449; hg19: chr6-29910698; COSMIC: COSV65137749;