Variant 6-29943337-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_002116.8(HLA-A):c.413G>A(p.Arg138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 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. R138E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.094 ( 625 hom., cov: 6)

Exomes 𝑓: 0.065 ( 17440 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -9.93

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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.413G>A	p.Arg138Gln	missense_variant	3/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1444C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.413G>A	p.Arg138Gln	missense_variant	3/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.0935

AC:

4247

AN:

45410

Hom.:

621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.0652

Gnomad AMR

AF:

0.0975

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.0393

Gnomad MID

AF:

0.125

Gnomad NFE

AF:

0.0634

Gnomad OTH

AF:

0.0785

GnomAD3 exomes

AF:

0.577

AC:

117957

AN:

204520

Hom.:

38163

AF XY:

0.571

AC XY:

63688

AN XY:

111592

show subpopulations

Gnomad AFR exome

AF:

0.601

Gnomad AMR exome

AF:

0.675

Gnomad ASJ exome

AF:

0.641

Gnomad EAS exome

AF:

0.674

Gnomad SAS exome

AF:

0.544

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.535

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0655

AC:

54969

AN:

839698

Hom.:

17440

Cov.:

AF XY:

0.0726

AC XY:

30390

AN XY:

418858

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.160

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.445

Gnomad4 SAS exome

AF:

0.214

Gnomad4 FIN exome

AF:

0.0547

Gnomad4 NFE exome

AF:

0.0381

Gnomad4 OTH exome

AF:

0.0846

GnomAD4 genome

AF:

0.0937

AC:

4261

AN:

45454

Hom.:

625

Cov.:

AF XY:

0.0922

AC XY:

2022

AN XY:

21930

show subpopulations

Gnomad4 AFR

AF:

0.155

Gnomad4 AMR

AF:

0.0985

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.161

Gnomad4 SAS

AF:

0.135

Gnomad4 FIN

AF:

0.0393

Gnomad4 NFE

AF:

0.0634

Gnomad4 OTH

AF:

0.0794

Alfa

AF:

0.502

Hom.:

3816

ESP6500AA

AF:

0.579

AC:

1722

ESP6500EA

AF:

0.463

AC:

2497

ExAC

AF:

0.535

AC:

63404

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.0

DANN

Benign

0.84

DEOGEN2

Benign

0.025

T;T;T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.0090

.;T;T;T;T

MetaRNN

Benign

0.000074

T;T;T;T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.29

PROVEAN

Benign

0.37

N;N;N;N;.

REVEL

Benign

0.047

Sift

Benign

0.33

T;T;T;.;.

Sift4G

Benign

0.31

T;T;T;T;.

Polyphen

0.0020

B;P;B;B;.

Vest4

0.064

MPC

0.095

ClinPred

0.0087

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: 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