chr6-29942985-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002116.8(HLA-A):c.302A>G(p.Asp101Gly) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D101N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 102 hom., cov: 5)

Exomes 𝑓: 0.045 ( 3875 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.47

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002359569).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0285 (1474/51706) while in subpopulation NFE AF= 0.0349 (934/26754). AF 95% confidence interval is 0.0331. There are 102 homozygotes in gnomad4. There are 701 alleles in male gnomad4 subpopulation. Median coverage is 5. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1474 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.302A>G	p.Asp101Gly	missense_variant	Exon 2 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1796T>C		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.302A>G	p.Asp101Gly	missense_variant	Exon 2 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

1471

AN:

51686

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.0443

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.00624

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.0119

Gnomad NFE

AF:

0.0349

Gnomad OTH

AF:

0.0219

GnomAD3 exomes

AF:

0.0422

AC:

9524

AN:

225872

Hom.:

267

AF XY:

0.0432

AC XY:

5287

AN XY:

122328

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.0302

Gnomad ASJ exome

AF:

0.0493

Gnomad EAS exome

AF:

0.00511

Gnomad SAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0539

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0452

AC:

45097

AN:

998028

Hom.:

3875

Cov.:

AF XY:

0.0457

AC XY:

22572

AN XY:

494100

show subpopulations

Gnomad4 AFR exome

AF:

0.0136

Gnomad4 AMR exome

AF:

0.0323

Gnomad4 ASJ exome

AF:

0.0457

Gnomad4 EAS exome

AF:

0.00381

Gnomad4 SAS exome

AF:

0.0387

Gnomad4 FIN exome

AF:

0.0449

Gnomad4 NFE exome

AF:

0.0479

Gnomad4 OTH exome

AF:

0.0425

GnomAD4 genome

AF:

0.0285

AC:

1474

AN:

51706

Hom.:

102

Cov.:

AF XY:

0.0277

AC XY:

701

AN XY:

25342

show subpopulations

Gnomad4 AFR

AF:

0.0166

Gnomad4 AMR

AF:

0.0301

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.00626

Gnomad4 SAS

AF:

0.0286

Gnomad4 FIN

AF:

0.0252

Gnomad4 NFE

AF:

0.0349

Gnomad4 OTH

AF:

0.0219

Alfa

AF:

0.0436

Hom.:

ExAC

AF:

0.0417

AC:

4828

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.0

DANN

Benign

0.48

DEOGEN2

Benign

0.039

T;T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.034

.;T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T;T

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

N;N;N;N;.

REVEL

Benign

0.091

Sift

Benign

0.068

T;T;T;.;.

Sift4G

Benign

0.17

T;T;T;T;.

Polyphen

0.058

B;B;B;B;.

Vest4

0.060

MPC

0.17

ClinPred

0.0074

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

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