Variant chr6-29943451-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E176A) has been classified as Likely benign.

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

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:

LOC124901298 (HGNC:):

LOC124901298 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.527A>T	p.Glu176Val	missense_variant	3/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1330T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.527A>T	p.Glu176Val	missense_variant	3/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

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

GnomAD3 exomes

AF:

0.566

AC:

130577

AN:

230672

Hom.:

35128

AF XY:

0.557

AC XY:

70294

AN XY:

126272

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 SAS exome

AF:

0.537

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

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.399

Gnomad4 ASJ exome

AF:

0.247

Gnomad4 EAS exome

AF:

0.434

Gnomad4 SAS exome

AF:

0.345

Gnomad4 FIN exome

AF:

0.0955

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.106

AC:

3985

AN:

37772

Hom.:

512

Cov.:

AF XY:

0.104

AC XY:

1899

AN XY:

18180

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.168

Gnomad4 ASJ

AF:

0.204

Gnomad4 EAS

AF:

0.179

Gnomad4 SAS

AF:

0.246

Gnomad4 FIN

AF:

0.0317

Gnomad4 NFE

AF:

0.0810

Gnomad4 OTH

AF:

0.108

Alfa

AF:

0.461

Hom.:

1761

ExAC

AF:

0.532

AC:

62925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0020

DANN

Benign

0.50

DEOGEN2

Benign

0.023

T;T;T;T;.

Eigen

Benign

-3.4

Eigen_PC

Benign

-3.6

FATHMM_MKL

Benign

0.00089

LIST_S2

Benign

0.0036

.;T;T;T;T

MetaRNN

Benign

0.0000048

T;T;T;T;T

MetaSVM

Benign

-0.52

PrimateAI

Benign

0.30

PROVEAN

Benign

0.050

N;N;N;N;.

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

0.71

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over