6-29949662-T-C

Variant names:

• chr6-29949662-T-C
• rs2517715
• ENST00000706904.1:c.*1973T>C

Variant summary

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

The ENST00000706904.1(HLA-A):​c.*1973T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 151,656 control chromosomes in the GnomAD database, including 7,963 homozygotes. 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 0.32 (7963 hom., cov: 31)
• Consequence: HLA-A ENST00000706904.1 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A 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 the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, 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. More than 6000 HLA-A 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 (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000706904.1	c.*1973T>C		downstream_gene_variant				ENSP00000516615.1
HLA-A	ENST00000706902.1	n.*1887T>C		downstream_gene_variant				ENSP00000516613.1
HLA-A	ENST00000706903.1	n.*1159T>C		downstream_gene_variant				ENSP00000516614.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48426 AN: 151540 Hom.: 7962 Cov.: 31

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.299

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.319 AC: 48443 AN: 151656 Hom.: 7963 Cov.: 31 AF XY: 0.318 AC XY: 23536 AN XY: 74100

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.338

Gnomad4 OTH AF: 0.295

Alfa AF: 0.330 Hom.: 3785

Bravo AF: 0.316

Asia WGS AF: 0.230 AC: 799 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2517715; hg19: chr6-29917439;