6-29942994-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):c.311C>T(p.Thr104Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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).

Frequency

Genomes: 𝑓 0.000022 ( 0 hom., cov: 2)

Exomes 𝑓: 0.000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.44

Publications

11 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002553463).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	NM_002116.8	MANE Select	c.311C>T	p.Thr104Ile	missense	Exon 2 of 8	NP_002107.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.311C>T	p.Thr104Ile	missense	Exon 2 of 8	ENSP00000366005.5	P04439-1
HLA-A	ENST00000952344.1		c.311C>T	p.Thr104Ile	missense	Exon 2 of 8	ENSP00000622403.1
HLA-A	ENST00000706894.1		c.311C>T	p.Thr104Ile	missense	Exon 3 of 8	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes

AF:

0.0000223

AC:

AN:

44862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000182

AC:

AN:

219584

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.000218

Gnomad AMR exome

AF:

0.000102

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.000317

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.000746

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000958

AC:

AN:

751744

Hom.:

Cov.:

AF XY:

0.0000835

AC XY:

AN XY:

371170

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000112

AC:

AN:

17824

American (AMR)

AF:

0.000183

AC:

AN:

16350

Ashkenazi Jewish (ASJ)

AF:

0.000263

AC:

AN:

11400

East Asian (EAS)

AF:

0.000189

AC:

AN:

10568

South Asian (SAS)

AF:

0.000139

AC:

AN:

43256

European-Finnish (FIN)

AF:

0.0000335

AC:

AN:

29816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2266

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

590556

Other (OTH)

AF:

0.000101

AC:

AN:

29708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.294

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000223

AC:

AN:

44868

Hom.:

Cov.:

AF XY:

0.0000453

AC XY:

AN XY:

22076

show subpopulations

African (AFR)

AF:

0.000104

AC:

AN:

9628

American (AMR)

AF:

0.00

AC:

AN:

3034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

844

East Asian (EAS)

AF:

0.00

AC:

AN:

1422

South Asian (SAS)

AF:

0.00

AC:

AN:

1284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

23062

Other (OTH)

AF:

0.00

AC:

AN:

550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00163

AC:

139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.6

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.021

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.020

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.94

PhyloP100

-4.4

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.041

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.11

MVP

0.099

MPC

0.091

ClinPred

0.017

GERP RS

-7.1

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over