rs7745413

Positions:

• chr6-29947692-T-C

Variant summary

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

The ENST00000706904.1(HLA-A):​c.*3T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 150,846 control chromosomes in the GnomAD database, including 5,076 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 0.25 (5076 hom., cov: 32)
• Consequence: HLA-A ENST00000706904.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.190

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000706904.1	c.*3T>C		3_prime_UTR_variant	9/9			ENSP00000516615	A1
HLA-A	ENST00000706902.1	c.*3T>C		3_prime_UTR_variant, NMD_transcript_variant	9/10			ENSP00000516613
HLA-A	ENST00000706903.1	c.*135T>C		3_prime_UTR_variant, NMD_transcript_variant	10/11			ENSP00000516614

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37610 AN: 150728 Hom.: 5054 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.250 AC: 37676 AN: 150846 Hom.: 5076 Cov.: 32 AF XY: 0.253 AC XY: 18635 AN XY: 73712

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.375

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.276

Alfa AF: 0.233 Hom.: 395

Bravo AF: 0.259

Asia WGS AF: 0.454 AC: 1574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7745413; hg19: chr6-29915469;