chr6-29942594-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.41C>T(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.065 ( 266 hom., cov: 17)

Exomes 𝑓: 0.032 ( 2894 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.59

Publications

23 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:

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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=0.002488315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.41C>T	p.Ser14Leu	missense_variant	Exon 1 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+2187G>A		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.41C>T	p.Ser14Leu	missense_variant	Exon 1 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.0649

AC:

6378

AN:

98204

Hom.:

265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0867

Gnomad AMI

AF:

0.0550

Gnomad AMR

AF:

0.0746

Gnomad ASJ

AF:

0.0635

Gnomad EAS

AF:

0.0666

Gnomad SAS

AF:

0.0924

Gnomad FIN

AF:

0.0401

Gnomad MID

AF:

0.0787

Gnomad NFE

AF:

0.0520

Gnomad OTH

AF:

0.0707

GnomAD2 exomes

AF:

0.123

AC:

27925

AN:

226232

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.0834

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0317

AC:

30255

AN:

952964

Hom.:

2894

Cov.:

AF XY:

0.0336

AC XY:

15944

AN XY:

474150

show subpopulations

African (AFR)

AF:

0.0651

AC:

1407

AN:

21616

American (AMR)

AF:

0.0661

AC:

1329

AN:

20120

Ashkenazi Jewish (ASJ)

AF:

0.0447

AC:

683

AN:

15280

East Asian (EAS)

AF:

0.0539

AC:

1169

AN:

21696

South Asian (SAS)

AF:

0.0586

AC:

3320

AN:

56634

European-Finnish (FIN)

AF:

0.0429

AC:

1464

AN:

34104

Middle Eastern (MID)

AF:

0.0421

AC:

148

AN:

3516

European-Non Finnish (NFE)

AF:

0.0259

AC:

19150

AN:

739748

Other (OTH)

AF:

0.0394

AC:

1585

AN:

40250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

1601

3203

4804

6406

8007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0651

AC:

6391

AN:

98236

Hom.:

266

Cov.:

AF XY:

0.0627

AC XY:

2972

AN XY:

47382

show subpopulations

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

African (AFR)

AF:

0.0868

AC:

2330

AN:

26846

American (AMR)

AF:

0.0748

AC:

643

AN:

8602

Ashkenazi Jewish (ASJ)

AF:

0.0635

AC:

140

AN:

2204

East Asian (EAS)

AF:

0.0674

AC:

215

AN:

3188

South Asian (SAS)

AF:

0.0924

AC:

283

AN:

3062

European-Finnish (FIN)

AF:

0.0401

AC:

265

AN:

6612

Middle Eastern (MID)

AF:

0.0842

AC:

AN:

202

European-Non Finnish (NFE)

AF:

0.0520

AC:

2372

AN:

45604

Other (OTH)

AF:

0.0709

AC:

AN:

1298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.356

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0651

Hom.:

TwinsUK

AF:

0.103

AC:

383

ALSPAC

AF:

0.109

AC:

420

ESP6500AA

AF:

0.166

AC:

731

ESP6500EA

AF:

0.106

AC:

907

ExAC

AF:

0.118

AC:

14345

Asia WGS

AF:

0.134

AC:

465

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.9

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.034

T;T;T;T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.00099

LIST_S2

Benign

0.25

.;T;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T;T

MetaSVM

Benign

-0.85

PhyloP100

-4.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;N;N;N;.

REVEL

Benign

0.050

Sift

Benign

0.13

T;T;T;.;.

Sift4G

Benign

0.11

T;T;T;T;.

Polyphen

0.0020

B;D;B;D;.

Vest4

0.070

MPC

0.074

ClinPred

0.037

GERP RS

-1.4

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.11

Mutation Taster

=100/0

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

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chr6-29942594-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over