Genetic Variant NM_002116.8:c.282G>C (chr6-29942965-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002116.8(HLA-A):c.282G>C(p.Gln94His) 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.

Frequency

Genomes: 𝑓 0.41 ( 6970 hom., cov: 8)

Exomes 𝑓: 0.60 ( 232696 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.69

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:

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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=1.1530621E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.282G>C	p.Gln94His	missense_variant	Exon 2 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1816C>G		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.282G>C	p.Gln94His	missense_variant	Exon 2 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

25136

AN:

60800

Hom.:

6946

Cov.:

show subpopulations

Gnomad AFR

AF:

0.568

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.462

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.279

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.463

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.425

GnomAD3 exomes

AF:

0.701

AC:

166986

AN:

238122

Hom.:

59063

AF XY:

0.698

AC XY:

90221

AN XY:

129246

show subpopulations

Gnomad AFR exome

AF:

0.664

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.727

Gnomad EAS exome

AF:

0.677

Gnomad SAS exome

AF:

0.678

Gnomad FIN exome

AF:

0.630

Gnomad NFE exome

AF:

0.708

Gnomad OTH exome

AF:

0.687

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.599

AC:

586495

AN:

978738

Hom.:

232696

Cov.:

AF XY:

0.599

AC XY:

293013

AN XY:

489330

show subpopulations

Gnomad4 AFR exome

AF:

0.628

Gnomad4 AMR exome

AF:

0.684

Gnomad4 ASJ exome

AF:

0.648

Gnomad4 EAS exome

AF:

0.587

Gnomad4 SAS exome

AF:

0.639

Gnomad4 FIN exome

AF:

0.333

Gnomad4 NFE exome

AF:

0.603

Gnomad4 OTH exome

AF:

0.596

GnomAD4 genome

AF:

0.414

AC:

25198

AN:

60868

Hom.:

6970

Cov.:

AF XY:

0.404

AC XY:

11904

AN XY:

29498

show subpopulations

Gnomad4 AFR

AF:

0.569

Gnomad4 AMR

AF:

0.463

Gnomad4 ASJ

AF:

0.432

Gnomad4 EAS

AF:

0.280

Gnomad4 SAS

AF:

0.421

Gnomad4 FIN

AF:

0.140

Gnomad4 NFE

AF:

0.351

Gnomad4 OTH

AF:

0.425

Alfa

AF:

0.659

Hom.:

5772

ESP6500AA

AF:

0.605

AC:

2661

ESP6500EA

AF:

0.655

AC:

5625

ExAC

AF:

0.654

AC:

79293

Asia WGS

AF:

0.673

AC:

2338

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.0

DANN

Benign

0.39

DEOGEN2

Benign

0.021

T;T;T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.0088

.;T;T;T;T

MetaRNN

Benign

0.000012

T;T;T;T;T

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.35

PROVEAN

Benign

0.30

N;N;N;N;.

REVEL

Benign

0.044

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

0.67

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.10

MutPred

0.11

Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);

MPC

0.078

ClinPred

0.0021

GERP RS

-0.59

Varity_R

0.23

gMVP

0.13

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