dbSNP rs1131118: HLA-C:p.Arg121Trp (chr6-31271331-T-A) – 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.361A>T(p.Arg121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. 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 0.047 ( 382 hom., cov: 5)

Exomes 𝑓: 0.17 ( 43773 hom. )

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -10.4

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=0.005865842).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.361A>T	p.Arg121Trp	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.361A>T	p.Arg121Trp	missense_variant	Exon 3 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

2593

AN:

55198

Hom.:

377

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0381

Gnomad AMR

AF:

0.0400

Gnomad ASJ

AF:

0.0800

Gnomad EAS

AF:

0.0327

Gnomad SAS

AF:

0.0327

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.0714

Gnomad NFE

AF:

0.0306

Gnomad OTH

AF:

0.0550

GnomAD3 exomes

AF:

0.249

AC:

58162

AN:

233900

Hom.:

6639

AF XY:

0.252

AC XY:

32338

AN XY:

128176

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.228

Gnomad ASJ exome

AF:

0.403

Gnomad EAS exome

AF:

0.288

Gnomad SAS exome

AF:

0.279

Gnomad FIN exome

AF:

0.186

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.173

AC:

138543

AN:

801260

Hom.:

43773

Cov.:

AF XY:

0.183

AC XY:

73945

AN XY:

404564

show subpopulations

Gnomad4 AFR exome

AF:

0.274

Gnomad4 AMR exome

AF:

0.277

Gnomad4 ASJ exome

AF:

0.436

Gnomad4 EAS exome

AF:

0.374

Gnomad4 SAS exome

AF:

0.292

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.144

Gnomad4 OTH exome

AF:

0.189

GnomAD4 genome

AF:

0.0472

AC:

2609

AN:

55244

Hom.:

382

Cov.:

AF XY:

0.0464

AC XY:

1226

AN XY:

26416

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.0400

Gnomad4 ASJ

AF:

0.0800

Gnomad4 EAS

AF:

0.0329

Gnomad4 SAS

AF:

0.0325

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0306

Gnomad4 OTH

AF:

0.0565

Alfa

AF:

0.178

Hom.:

460

ESP6500AA

AF:

0.224

AC:

967

ESP6500EA

AF:

0.229

AC:

1933

ExAC

AF:

0.245

AC:

29468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.33

DANN

Benign

0.62

DEOGEN2

Benign

0.023

T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.017

T;T

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.94

N;N

REVEL

Benign

0.22

Sift

Benign

0.28

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.030

B;B

Vest4

0.067

MPC

0.53

ClinPred

0.015

GERP RS

-5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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