Variant 6-29942984-G-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.301G>A(p.Asp101Asn) 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. D101S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.23 ( 2166 hom., cov: 5)

Exomes 𝑓: 0.41 ( 111284 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.38

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=0.0089042485).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.301G>A	p.Asp101Asn	missense_variant	2/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1797C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.301G>A	p.Asp101Asn	missense_variant	2/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

10636

AN:

45876

Hom.:

2156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.300

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.265

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.0730

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.373

AC:

84634

AN:

227064

Hom.:

16360

AF XY:

0.379

AC XY:

46793

AN XY:

123314

show subpopulations

Gnomad AFR exome

AF:

0.361

Gnomad AMR exome

AF:

0.374

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.228

Gnomad SAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.393

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.407

AC:

357115

AN:

876508

Hom.:

111284

Cov.:

AF XY:

0.407

AC XY:

177341

AN XY:

435366

show subpopulations

Gnomad4 AFR exome

AF:

0.357

Gnomad4 AMR exome

AF:

0.361

Gnomad4 ASJ exome

AF:

0.514

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.400

Gnomad4 FIN exome

AF:

0.195

Gnomad4 NFE exome

AF:

0.423

Gnomad4 OTH exome

AF:

0.420

GnomAD4 genome

AF:

0.232

AC:

10660

AN:

45888

Hom.:

2166

Cov.:

AF XY:

0.219

AC XY:

4956

AN XY:

22658

show subpopulations

Gnomad4 AFR

AF:

0.302

Gnomad4 AMR

AF:

0.266

Gnomad4 ASJ

AF:

0.291

Gnomad4 EAS

AF:

0.0558

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.0730

Gnomad4 NFE

AF:

0.236

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.383

Hom.:

2716

ESP6500AA

AF:

0.268

AC:

1178

ESP6500EA

AF:

0.314

AC:

2688

ExAC

AF:

0.351

AC:

41456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.2

DANN

Benign

0.79

DEOGEN2

Benign

0.022

T;T;T;T;.

Eigen

Benign

-2.9

Eigen_PC

Benign

-2.9

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.015

.;T;T;T;T

MetaRNN

Benign

0.0089

T;T;T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.32

PROVEAN

Benign

1.1

N;N;N;N;.

REVEL

Benign

0.013

Sift

Benign

0.77

T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.045

MPC

0.081

ClinPred

0.0021

GERP RS

-7.2

Varity_R

0.27

gMVP

0.10

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