chr6-29943426-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002116.8(HLA-A):c.502A>C(p.Lys168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.23 ( 3083 hom., cov: 5)

Exomes 𝑓: 0.20 ( 39169 hom. )

Consequence

HLA-A
NM_002116.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.509

Publications

29 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:

POLR1HASP (HGNC:):

POLR1HASP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.544186E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.502A>C	p.Lys168Gln	missense_variant	Exon 3 of 8	ENST00000376809.10	NP_002107.3	P04439-1B1PKY1B2R7U3
LOC124901298	XR_007059541.1 link	n.813+1355T>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.502A>C	p.Lys168Gln	missense_variant	Exon 3 of 8	6	NM_002116.8	ENSP00000366005.5		P04439-1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

9512

AN:

41280

Hom.:

3063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.528

Gnomad AMI

AF:

0.0357

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.258

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.294

GnomAD2 exomes

AF:

0.244

AC:

57574

AN:

235986

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.531

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.223

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.255

GnomAD4 exome

AF:

0.199

AC:

132326

AN:

664514

Hom.:

39169

Cov.:

AF XY:

0.201

AC XY:

67987

AN XY:

338122

show subpopulations

African (AFR)

AF:

0.622

AC:

11480

AN:

18460

American (AMR)

AF:

0.329

AC:

6344

AN:

19302

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

3785

AN:

11894

East Asian (EAS)

AF:

0.407

AC:

6084

AN:

14944

South Asian (SAS)

AF:

0.242

AC:

12750

AN:

52624

European-Finnish (FIN)

AF:

0.0631

AC:

1776

AN:

28130

Middle Eastern (MID)

AF:

0.307

AC:

723

AN:

2354

European-Non Finnish (NFE)

AF:

0.168

AC:

82109

AN:

488492

Other (OTH)

AF:

0.257

AC:

7275

AN:

28314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

1170

2340

3510

4680

5850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2066

4132

6198

8264

10330

<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:

0.231

AC:

9559

AN:

41320

Hom.:

3083

Cov.:

AF XY:

0.216

AC XY:

4333

AN XY:

20056

show subpopulations

African (AFR)

AF:

0.529

AC:

5715

AN:

10804

American (AMR)

AF:

0.274

AC:

798

AN:

2910

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

161

AN:

788

East Asian (EAS)

AF:

0.259

AC:

203

AN:

784

South Asian (SAS)

AF:

0.174

AC:

135

AN:

774

European-Finnish (FIN)

AF:

0.0272

AC:

119

AN:

4370

Middle Eastern (MID)

AF:

0.364

AC:

AN:

European-Non Finnish (NFE)

AF:

0.112

AC:

2239

AN:

20032

Other (OTH)

AF:

0.300

AC:

147

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

120

240

360

480

600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

486

ExAC

AF:

0.238

AC:

28200

Asia WGS

AF:

0.260

AC:

901

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.019

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.034

T;T;T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.020

.;T;T;T;T

MetaRNN

Benign

0.000055

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.51

PrimateAI

Benign

0.28

PROVEAN

Benign

0.24

N;N;N;N;.

REVEL

Benign

0.025

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

0.93

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.034

MPC

0.088

ClinPred

0.0039

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.28

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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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