rs1131118

chr6-31271331-T-Achr6-31271331-T-Cchr6-31271331-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002117.6(HLA-C):c.361A>T(p.Arg121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 856,504 control chromosomes in the GnomAD database, including 44,155 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.047 (382 hom., cov: 5)
  • Exomes 𝑓: 0.17 (43773 hom.)
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -10.4

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]

ACMG classification

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/exons	MANE	UniProt
HLA-C	NM_002117.6	c.361A>T	p.Arg121Trp	missense_variant	3/8	ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.361A>T	p.Arg121Trp	missense_variant	3/8		NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 2593 AN: 55198 Hom.: 377 Cov.: 5

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

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.: 20 AF XY: 0.183 AC XY: 73945 AN XY: 404564

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.: 5 AF XY: 0.0464 AC XY: 1226 AN XY: 26416

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	T
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	N
LIST_S2	Benign	0.017	T;T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs1131118; hg19: chr6-31239108; COSMIC: COSV66110137; COSMIC: COSV66110137;