6-31271601-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.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 same amino acid change has been previously reported as Likely benignin 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

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=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/exons	MANE	UniProt
HLA-C	NM_002117.6	c.341A>C	p.Asp114Ala	missense_variant, splice_region_variant	2/8	ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.341A>C	p.Asp114Ala	missense_variant, splice_region_variant	2/8		NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.111 AC: 6206 AN: 55690 Hom.: 844 Cov.: 7

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

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.: 30 AF XY: 0.165 AC XY: 84724 AN XY: 514634

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.: 7 AF XY: 0.111 AC XY: 2933 AN XY: 26492

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	T
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	N
LIST_S2	Benign	0.0080	T;T
MetaRNN	Benign	0.000018	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs1131123; hg19: chr6-31239378; COSMIC: COSV66110096; COSMIC: COSV66110096;