Variant 6-29943287-A-G 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.363A>G(p.Ile121Met) 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. I121R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 1304 hom., cov: 5)

Exomes 𝑓: 0.14 ( 27444 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.67

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.371736E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.363A>G	p.Ile121Met	missense_variant	3/8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1494T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.363A>G	p.Ile121Met	missense_variant	3/8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

6383

AN:

43362

Hom.:

1297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.0595

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.597

AC:

119881

AN:

200820

Hom.:

42236

AF XY:

0.588

AC XY:

64643

AN XY:

109968

show subpopulations

Gnomad AFR exome

AF:

0.623

Gnomad AMR exome

AF:

0.785

Gnomad ASJ exome

AF:

0.646

Gnomad EAS exome

AF:

0.645

Gnomad SAS exome

AF:

0.591

Gnomad FIN exome

AF:

0.542

Gnomad NFE exome

AF:

0.527

Gnomad OTH exome

AF:

0.587

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.140

AC:

88000

AN:

628324

Hom.:

27444

Cov.:

AF XY:

0.151

AC XY:

47963

AN XY:

316988

show subpopulations

Gnomad4 AFR exome

AF:

0.176

Gnomad4 AMR exome

AF:

0.363

Gnomad4 ASJ exome

AF:

0.226

Gnomad4 EAS exome

AF:

0.441

Gnomad4 SAS exome

AF:

0.358

Gnomad4 FIN exome

AF:

0.151

Gnomad4 NFE exome

AF:

0.0989

Gnomad4 OTH exome

AF:

0.180

GnomAD4 genome

AF:

0.148

AC:

6402

AN:

43388

Hom.:

1304

Cov.:

AF XY:

0.145

AC XY:

3036

AN XY:

20994

show subpopulations

Gnomad4 AFR

AF:

0.202

Gnomad4 AMR

AF:

0.184

Gnomad4 ASJ

AF:

0.158

Gnomad4 EAS

AF:

0.179

Gnomad4 SAS

AF:

0.264

Gnomad4 FIN

AF:

0.0595

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.146

Alfa

AF:

0.466

Hom.:

2709

ESP6500AA

AF:

0.542

AC:

1609

ESP6500EA

AF:

0.455

AC:

2393

ExAC

AF:

0.513

AC:

58839

Asia WGS

AF:

0.705

AC:

2445

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.47

DANN

Benign

0.52

DEOGEN2

Benign

0.025

T;T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.0035

.;T;T;T;T

MetaRNN

Benign

0.0000094

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

1.2

N;N;N;N;.

REVEL

Benign

0.032

Sift

Benign

0.28

T;T;T;.;.

Sift4G

Benign

0.14

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.031

MPC

0.084

ClinPred

0.019

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

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