Genetic Variant HLA-C:p.Asp114Ala (chr6-31271601-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002117.6(HLA-C):c.341A>C(p.Asp114Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,085,990 control chromosomes in the GnomAD database, including 45,795 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.11 ( 845 hom., cov: 7)

Exomes 𝑓: 0.15 ( 44950 hom. )

Consequence

HLA-C
NM_002117.6 missense, splice_region

Scores

Splicing: ADA: 0.00007417

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.18

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7902476E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.341A>C	p.Asp114Ala	missense_variant, splice_region_variant	Exon 2 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.341A>C	p.Asp114Ala	missense_variant, splice_region_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

6206

AN:

55690

Hom.:

844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0758

Gnomad AMI

AF:

0.0442

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.0698

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.513

AC:

128111

AN:

249686

Hom.:

33523

AF XY:

0.512

AC XY:

69310

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.481

Gnomad AMR exome

AF:

0.515

Gnomad ASJ exome

AF:

0.561

Gnomad EAS exome

AF:

0.704

Gnomad SAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.486

Gnomad NFE exome

AF:

0.489

Gnomad OTH exome

AF:

0.520

GnomAD4 exome

AF:

0.155

AC:

159443

AN:

1030260

Hom.:

44950

Cov.:

AF XY:

0.165

AC XY:

84724

AN XY:

514634

show subpopulations

Gnomad4 AFR exome

AF:

0.159

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.438

Gnomad4 EAS exome

AF:

0.516

Gnomad4 SAS exome

AF:

0.321

Gnomad4 FIN exome

AF:

0.192

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.188

GnomAD4 genome

AF:

0.111

AC:

6208

AN:

55730

Hom.:

845

Cov.:

AF XY:

0.111

AC XY:

2933

AN XY:

26492

show subpopulations

Gnomad4 AFR

AF:

0.0759

Gnomad4 AMR

AF:

0.112

Gnomad4 ASJ

AF:

0.414

Gnomad4 EAS

AF:

0.189

Gnomad4 SAS

AF:

0.182

Gnomad4 FIN

AF:

0.0698

Gnomad4 NFE

AF:

0.108

Gnomad4 OTH

AF:

0.140

Alfa

AF:

0.445

Hom.:

6240

TwinsUK

AF:

0.480

AC:

1778

ALSPAC

AF:

0.478

AC:

1842

ExAC

AF:

0.513

AC:

62192

Asia WGS

AF:

0.546

AC:

1896

AN:

3476

EpiCase

AF:

0.468

EpiControl

AF:

0.483

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.45

DANN

Benign

0.71

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.0080

T;T

MetaRNN

Benign

0.000018

T;T

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.22

PROVEAN

Benign

4.0

N;N

REVEL

Uncertain

0.34

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.029

MPC

0.62

ClinPred

0.0011

GERP RS

-1.9

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000074

dbscSNV1_RF

Benign

0.020

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over