6-31271153-A-T

Position:

• chr6-31271153-A-T

Variant summary

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

The NM_002117.6(HLA-C):​c.539T>A​(p.Leu180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 897,654 control chromosomes in the GnomAD database, including 22,242 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L180D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (326 hom., cov: 3)
  • Exomes 𝑓: 0.11 (21916 hom.)
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.57

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=0.003414452).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.539T>A	p.Leu180Gln	missense_variant	3/8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.539T>A	p.Leu180Gln	missense_variant	3/8		NM_002117.6	ENSP00000365402	P4

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 1819 AN: 55680 Hom.: 326 Cov.: 3

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.0173

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.00205

Gnomad MID AF: 0.0521

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0394

GnomAD4 exome AF: 0.106 AC: 89201 AN: 841942 Hom.: 21916 Cov.: 29 AF XY: 0.103 AC XY: 43642 AN XY: 422034

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.0924

Gnomad4 EAS exome AF: 0.00464

Gnomad4 SAS exome AF: 0.0790

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0327 AC: 1821 AN: 55712 Hom.: 326 Cov.: 3 AF XY: 0.0308 AC XY: 818 AN XY: 26560

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.0421

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00205

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0389

ExAC AF: 0.0486 AC: 5726

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.099
DANN	Benign	0.40
DEOGEN2	Benign	0.026	T;.;.
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.0046	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.30	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.27	T;T;.
Sift4G	Benign	0.38	T;T;.
Polyphen		0.024	B;B;.
Vest4		0.090
MPC		0.55
ClinPred		0.0099	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs2308592; hg19: chr6-31238930; COSMIC: COSV66110810; COSMIC: COSV66110810;