6-29943451-A-T

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.527A>T(p.Glu176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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).

Frequency

Genomes: 𝑓 0.11 ( 512 hom., cov: 5)

Exomes 𝑓: 0.16 ( 20836 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -11.6

Publications

43 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:

POLR1HASP (HGNC:):

POLR1HASP 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=4.81467E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 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.527A>T	p.Glu176Val	missense	Exon 3 of 8	NP_002107.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.527A>T	p.Glu176Val	missense	Exon 3 of 8	ENSP00000366005.5	P04439-1
HLA-A	ENST00000952344.1		c.527A>T	p.Glu176Val	missense	Exon 3 of 8	ENSP00000622403.1
HLA-A	ENST00000706894.1		c.527A>T	p.Glu176Val	missense	Exon 4 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

3962

AN:

37744

Hom.:

503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.0437

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.0317

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.0810

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.566

AC:

130577

AN:

230672

AF XY:

0.557

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.732

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.573

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.157

AC:

110037

AN:

702262

Hom.:

20836

Cov.:

AF XY:

0.166

AC XY:

58566

AN XY:

353780

show subpopulations

African (AFR)

AF:

0.201

AC:

3547

AN:

17642

American (AMR)

AF:

0.399

AC:

7069

AN:

17730

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

3000

AN:

12154

East Asian (EAS)

AF:

0.434

AC:

6152

AN:

14170

South Asian (SAS)

AF:

0.345

AC:

16796

AN:

48688

European-Finnish (FIN)

AF:

0.0955

AC:

2584

AN:

27056

Middle Eastern (MID)

AF:

0.300

AC:

700

AN:

2330

European-Non Finnish (NFE)

AF:

0.122

AC:

65078

AN:

533362

Other (OTH)

AF:

0.175

AC:

5111

AN:

29130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1651

3302

4954

6605

8256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1834

3668

5502

7336

9170

<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:

0.106

AC:

3985

AN:

37772

Hom.:

512

Cov.:

AF XY:

0.104

AC XY:

1899

AN XY:

18180

show subpopulations

African (AFR)

AF:

0.141

AC:

1411

AN:

9996

American (AMR)

AF:

0.168

AC:

440

AN:

2622

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

151

AN:

742

East Asian (EAS)

AF:

0.179

AC:

120

AN:

670

South Asian (SAS)

AF:

0.246

AC:

165

AN:

672

European-Finnish (FIN)

AF:

0.0317

AC:

118

AN:

3726

Middle Eastern (MID)

AF:

0.218

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0810

AC:

1503

AN:

18560

Other (OTH)

AF:

0.108

AC:

AN:

454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.401

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.461

Hom.:

1761

ExAC

AF:

0.532

AC:

62925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0020

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.023

Eigen

Benign

-3.4

Eigen_PC

Benign

-3.6

FATHMM_MKL

Benign

0.00089

LIST_S2

Benign

0.0036

MetaRNN

Benign

0.0000048

MetaSVM

Benign

-0.52

PhyloP100

-12

PrimateAI

Benign

0.30

PROVEAN

Benign

0.050

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.032

MPC

0.097

ClinPred

0.0076

GERP RS

-7.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.64

gMVP

0.23

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over