Variant 6-29942982-T-A 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.299T>A(p.Val100Glu) 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. 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. V100A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 1011 hom., cov: 8)

Exomes 𝑓: 0.16 ( 21146 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.41

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005369067).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.299T>A	p.Val100Glu	missense_variant	2/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1799A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.299T>A	p.Val100Glu	missense_variant	2/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

12220

AN:

60812

Hom.:

1003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.331

Gnomad AMI

AF:

0.0650

Gnomad AMR

AF:

0.278

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.169

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.0448

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.235

GnomAD3 exomes

AF:

0.182

AC:

41399

AN:

227030

Hom.:

4060

AF XY:

0.182

AC XY:

22393

AN XY:

123256

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.249

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.182

Gnomad SAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.159

AC:

160527

AN:

1010210

Hom.:

21146

Cov.:

AF XY:

0.161

AC XY:

80828

AN XY:

502366

show subpopulations

Gnomad4 AFR exome

AF:

0.246

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.207

Gnomad4 EAS exome

AF:

0.254

Gnomad4 SAS exome

AF:

0.202

Gnomad4 FIN exome

AF:

0.0959

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.180

GnomAD4 genome

AF:

0.201

AC:

12266

AN:

60878

Hom.:

1011

Cov.:

AF XY:

0.195

AC XY:

5787

AN XY:

29666

show subpopulations

Gnomad4 AFR

AF:

0.332

Gnomad4 AMR

AF:

0.279

Gnomad4 ASJ

AF:

0.231

Gnomad4 EAS

AF:

0.170

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.0448

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.132

Hom.:

333

ExAC

AF:

0.173

AC:

21016

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.8

DANN

Benign

0.44

DEOGEN2

Benign

0.018

T;T;T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.027

.;T;T;T;T

MetaRNN

Benign

0.0054

T;T;T;T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.9

D;D;D;D;.

REVEL

Benign

0.079

Sift

Benign

0.37

T;T;T;.;.

Sift4G

Benign

0.19

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.083

MPC

0.14

ClinPred

0.010

GERP RS

-6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.17

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