NM_002117.6:c.361A>T

Variant names:

• chr6-31271331-T-A
• rs1131118
• NM_002117.6:c.361A>T

Variant summary

Our verdict is Benign. The variant received -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. 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 0.047 (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
• Publications: 28 publications found

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]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005865842).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.361A>T	p.Arg121Trp	missense_variant	Exon 3 of 8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.361A>T	p.Arg121Trp	missense_variant	Exon 3 of 8	6	NM_002117.6	ENSP00000365402.5

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

GnomAD2 exomes AF: 0.249 AC: 58162 AN: 233900 AF XY: 0.252

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 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

African (AFR) AF: 0.274 AC: 4514 AN: 16452

American (AMR) AF: 0.277 AC: 7209 AN: 25988

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 5123 AN: 11740

East Asian (EAS) AF: 0.374 AC: 6968 AN: 18624

South Asian (SAS) AF: 0.292 AC: 16182 AN: 55486

European-Finnish (FIN) AF: 0.129 AC: 3409 AN: 26528

Middle Eastern (MID) AF: 0.319 AC: 712 AN: 2234

European-Non Finnish (NFE) AF: 0.144 AC: 88267 AN: 611698

Other (OTH) AF: 0.189 AC: 6159 AN: 32510

GnomAD4 genome AF: 0.0472 AC: 2609 AN: 55244 Hom.: 382 Cov.: 5 AF XY: 0.0464 AC XY: 1226 AN XY: 26416

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

African (AFR) AF: 0.104 AC: 1207 AN: 11572

American (AMR) AF: 0.0400 AC: 202 AN: 5050

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 52 AN: 650

East Asian (EAS) AF: 0.0329 AC: 46 AN: 1398

South Asian (SAS) AF: 0.0325 AC: 49 AN: 1506

European-Finnish (FIN) AF: 0.0203 AC: 85 AN: 4182

Middle Eastern (MID) AF: 0.0714 AC: 6 AN: 84

European-Non Finnish (NFE) AF: 0.0306 AC: 912 AN: 29788

Other (OTH) AF: 0.0565 AC: 35 AN: 620

⚠️ 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.

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
PhyloP100		-10
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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