chr6-31271153-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002117.6(HLA-C):c.539T>G(p.Leu180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.0036 ( 3 hom., cov: 3)

Exomes 𝑓: 0.057 ( 9101 hom. )

Failed GnomAD Quality Control

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045161247).

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.539T>G	p.Leu180Arg	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>G	p.Leu180Arg	missense_variant	Exon 3 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

196

AN:

55054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.00442

Gnomad EAS

AF:

0.00982

Gnomad SAS

AF:

0.00448

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00350

Gnomad OTH

AF:

0.00735

GnomAD2 exomes

AF:

0.336

AC:

66999

AN:

199212

AF XY:

0.338

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.328

Gnomad ASJ exome

AF:

0.456

Gnomad EAS exome

AF:

0.334

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0574

AC:

48545

AN:

845214

Hom.:

9101

Cov.:

AF XY:

0.0634

AC XY:

26800

AN XY:

422888

show subpopulations

African (AFR)

AF:

0.0655

AC:

1156

AN:

17650

American (AMR)

AF:

0.107

AC:

2752

AN:

25798

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

1934

AN:

10496

East Asian (EAS)

AF:

0.166

AC:

2597

AN:

15616

South Asian (SAS)

AF:

0.159

AC:

8564

AN:

53880

European-Finnish (FIN)

AF:

0.0602

AC:

1470

AN:

24428

Middle Eastern (MID)

AF:

0.0953

AC:

225

AN:

2360

European-Non Finnish (NFE)

AF:

0.0420

AC:

27739

AN:

660820

Other (OTH)

AF:

0.0617

AC:

2108

AN:

34166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

910

1820

2731

3641

4551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.00358

AC:

197

AN:

55088

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

AN XY:

26278

show subpopulations

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

African (AFR)

AF:

0.00328

AC:

AN:

11598

American (AMR)

AF:

0.00328

AC:

AN:

5180

Ashkenazi Jewish (ASJ)

AF:

0.00442

AC:

AN:

678

East Asian (EAS)

AF:

0.00988

AC:

AN:

1316

South Asian (SAS)

AF:

0.00446

AC:

AN:

1570

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

3836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00350

AC:

104

AN:

29734

Other (OTH)

AF:

0.00875

AC:

AN:

686

⚠️ 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: 0.268

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.329

AC:

38713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.073

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.024

T;.;.

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.6

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.0037

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.99

PhyloP100

-5.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.39

N;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.54

T;T;.

Sift4G

Benign

0.42

T;T;.

Polyphen

0.010

B;B;.

Vest4

0.075

MPC

0.74

ClinPred

0.0052

GERP RS

-5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.23

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over