6-31271153-A-T

Variant names:

Variant summary

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

The NM_002117.6(HLA-C):c.539T>A(p.Leu180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 897,654 control chromosomes in the GnomAD database, including 22,242 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L180L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.033 ( 326 hom., cov: 3)

Exomes 𝑓: 0.11 ( 21916 hom. )

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.57

Publications

25 publications found

Variant links:

Genes affected

HLA-C (HGNC:4933): (major histocompatibility complex, class I, C) HLA-C 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 endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, 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. About 6000 HLA-C 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-C links:

ENSG00000298396 (HGNC:):

ENSG00000298396 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=0.003414452).

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.539T>A	p.Leu180Gln	missense_variant	Exon 3 of 8	ENST00000376228.10	NP_002108.4	P10321-1Q6R739Q95HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10 link	c.539T>A	p.Leu180Gln	missense_variant	Exon 3 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.0327

AC:

1819

AN:

55680

Hom.:

326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0672

Gnomad AMI

AF:

0.0173

Gnomad AMR

AF:

0.0419

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.00205

Gnomad MID

AF:

0.0521

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0394

GnomAD2 exomes

AF:

0.0429

AC:

8541

AN:

199212

AF XY:

0.0420

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.0564

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00347

Gnomad FIN exome

AF:

0.00681

Gnomad NFE exome

AF:

0.0463

Gnomad OTH exome

AF:

0.0498

GnomAD4 exome

AF:

0.106

AC:

89201

AN:

841942

Hom.:

21916

Cov.:

AF XY:

0.103

AC XY:

43642

AN XY:

422034

show subpopulations

African (AFR)

AF:

0.252

AC:

4505

AN:

17904

American (AMR)

AF:

0.116

AC:

3082

AN:

26638

Ashkenazi Jewish (ASJ)

AF:

0.0924

AC:

1009

AN:

10922

East Asian (EAS)

AF:

0.00464

AC:

AN:

16602

South Asian (SAS)

AF:

0.0790

AC:

4397

AN:

55692

European-Finnish (FIN)

AF:

0.0154

AC:

393

AN:

25456

Middle Eastern (MID)

AF:

0.123

AC:

301

AN:

2438

European-Non Finnish (NFE)

AF:

0.110

AC:

71824

AN:

652078

Other (OTH)

AF:

0.106

AC:

3613

AN:

34212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1315

2630

3944

5259

6574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2430

4860

7290

9720

12150

<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:

0.0327

AC:

1821

AN:

55712

Hom.:

326

Cov.:

AF XY:

0.0308

AC XY:

818

AN XY:

26560

show subpopulations

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

African (AFR)

AF:

0.0670

AC:

764

AN:

11398

American (AMR)

AF:

0.0421

AC:

218

AN:

5182

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

702

East Asian (EAS)

AF:

0.00

AC:

AN:

1390

South Asian (SAS)

AF:

0.0112

AC:

AN:

1604

European-Finnish (FIN)

AF:

0.00205

AC:

AN:

3910

Middle Eastern (MID)

AF:

0.0532

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0250

AC:

758

AN:

30334

Other (OTH)

AF:

0.0389

AC:

AN:

694

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.326

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00

Hom.:

ExAC

AF:

0.0486

AC:

5726

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.099

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.026

T;.;.

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.0046

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.98

PhyloP100

-5.6

PrimateAI

Benign

0.29

PROVEAN

Benign

0.30

N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.27

T;T;.

Sift4G

Benign

0.38

T;T;.

Polyphen

0.024

B;B;.

Vest4

0.090

MPC

0.55

ClinPred

0.0099

GERP RS

-5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.12

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