rs1050384

Positions:

• chr6-31271305-G-C
• chr6-31271305-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_002117.6(HLA-C):​c.387C>G​(p.Pro129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 6)
  • Exomes 𝑓: 0.0073 (287 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.48

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP7: Synonymous conserved (PhyloP=-6.48 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-C	NM_002117.6	c.387C>G	p.Pro129=	synonymous_variant	3/8	ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.387C>G	p.Pro129=	synonymous_variant	3/8		NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 121 AN: 62276 Hom.: 1 Cov.: 6

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00655

Gnomad AMR AF: 0.00213

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00665

Gnomad SAS AF: 0.00238

Gnomad FIN AF: 0.00163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000734

Gnomad OTH AF: 0.00535

GnomAD3 exomes AF: 0.141 AC: 31387 AN: 222356 Hom.: 331 AF XY: 0.138 AC XY: 16781 AN XY: 121466

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.0743

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.138

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00729 AC: 7209 AN: 988374 Hom.: 287 Cov.: 28 AF XY: 0.00795 AC XY: 3941 AN XY: 495880

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0254

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00193 AC: 120 AN: 62308 Hom.: 1 Cov.: 6 AF XY: 0.00195 AC XY: 58 AN XY: 29720

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.00213

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00670

Gnomad4 SAS AF: 0.00238

Gnomad4 FIN AF: 0.00163

Gnomad4 NFE AF: 0.000734

Gnomad4 OTH AF: 0.00529

Alfa AF: 0.130 Hom.: 28

Asia WGS AF: 0.186 AC: 648 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	9.8
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1050384; hg19: chr6-31239082; COSMIC: COSV66112659; COSMIC: COSV66112659;