rs1059449

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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.

Frequency

Genomes: 𝑓 0.089 ( 553 hom., cov: 15)

Exomes 𝑓: 0.052 ( 3740 hom. )

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.24

Publications

23 publications found

Variant links:

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]

HLA-A links:

ENSG00000227766 (HGNC:):

ENSG00000227766 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.238G>A	p.Gly80Arg	missense_variant	Exon 2 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1860C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.238G>A	p.Gly80Arg	missense_variant	Exon 2 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.0887

AC:

8849

AN:

99760

Hom.:

550

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0508

AC XY:

34796

AN XY:

685360

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1698

3396

5093

6791

8489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1982

3964

5946

7928

9910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0889

AC:

8874

AN:

99856

Hom.:

553

Cov.:

AF XY:

0.0871

AC XY:

4210

AN XY:

48350

show subpopulations

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:

AN:

210

European-Non Finnish (NFE)

AF:

0.0546

AC:

2420

AN:

44322

Other (OTH)

AF:

0.104

AC:

140

AN:

1346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

T;T;T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.23

.;T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.2

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-6.7

D;D;D;D;.

REVEL

Benign

0.048

Sift

Benign

0.036

D;D;D;.;.

Sift4G

Uncertain

0.019

D;D;D;D;.

Polyphen

0.81

P;P;P;P;.

Vest4

0.11

MutPred

0.74

Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);Gain of solvent accessibility (P = 0.0263);

MPC

0.38

ClinPred

0.093

GERP RS

2.8

PromoterAI

0.037

Neutral

(source)

Varity_R

0.37

gMVP

0.18

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over