Genetic Variant HLA-C:p.Thr363Ala (chr6-31269347-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_002117.6(HLA-C):c.1087A>G(p.Thr363Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 470 hom., cov: 4)

Exomes 𝑓: 0.092 ( 25967 hom. )

Failed GnomAD Quality Control

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

Publications

48 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:

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=8.327648E-6).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.1087A>G	p.Thr363Ala	missense_variant	Exon 7 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.1087A>G	p.Thr363Ala	missense_variant	Exon 7 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

4149

AN:

39446

Hom.:

464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.0781

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.286

Gnomad NFE

AF:

0.0831

Gnomad OTH

AF:

0.139

GnomAD2 exomes

AF:

0.731

AC:

181760

AN:

248666

AF XY:

0.731

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.756

Gnomad ASJ exome

AF:

0.873

Gnomad EAS exome

AF:

0.802

Gnomad FIN exome

AF:

0.714

Gnomad NFE exome

AF:

0.684

Gnomad OTH exome

AF:

0.739

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0923

AC:

56322

AN:

609992

Hom.:

25967

Cov.:

AF XY:

0.0988

AC XY:

30018

AN XY:

303926

show subpopulations

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

African (AFR)

AF:

0.311

AC:

3249

AN:

10446

American (AMR)

AF:

0.206

AC:

3369

AN:

16378

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

2467

AN:

6720

East Asian (EAS)

AF:

0.434

AC:

5769

AN:

13284

South Asian (SAS)

AF:

0.222

AC:

7203

AN:

32446

European-Finnish (FIN)

AF:

0.133

AC:

3038

AN:

22814

Middle Eastern (MID)

AF:

0.246

AC:

415

AN:

1688

European-Non Finnish (NFE)

AF:

0.0577

AC:

27816

AN:

482134

Other (OTH)

AF:

0.124

AC:

2996

AN:

24082

⚠️ 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: 0.270

Heterozygous variant carriers

661

1322

1984

2645

3306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.105

AC:

4164

AN:

39512

Hom.:

470

Cov.:

AF XY:

0.101

AC XY:

1889

AN XY:

18698

show subpopulations

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

African (AFR)

AF:

0.140

AC:

1050

AN:

7504

American (AMR)

AF:

0.114

AC:

385

AN:

3364

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

AN:

506

East Asian (EAS)

AF:

0.166

AC:

151

AN:

910

South Asian (SAS)

AF:

0.129

AC:

131

AN:

1012

European-Finnish (FIN)

AF:

0.137

AC:

384

AN:

2812

Middle Eastern (MID)

AF:

0.294

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0831

AC:

1875

AN:

22572

Other (OTH)

AF:

0.140

AC:

AN:

444

⚠️ 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: 0.266

Heterozygous variant carriers

365

730

1094

1459

1824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.700

Hom.:

85300

TwinsUK

AF:

0.656

AC:

2431

ALSPAC

AF:

0.654

AC:

2520

ESP6500AA

AF:

0.793

AC:

2396

ESP6500EA

AF:

0.687

AC:

3724

ExAC

AF:

0.731

AC:

88627

Asia WGS

AF:

0.766

AC:

2667

AN:

3478

EpiCase

AF:

0.686

EpiControl

AF:

0.705

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.20

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.00059

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.52

T;T;T

MetaRNN

Benign

0.0000083

T;T;T

MetaSVM

Benign

-0.99

PhyloP100

-1.3

PrimateAI

Benign

0.25

PROVEAN

Benign

0.38

N;N;.

REVEL

Benign

0.016

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.022

MPC

0.48

ClinPred

0.00019

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.067

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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