6-29948728-C-T

Variant summary

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

The ENST00000706904.1(HLA-A):c.*1039C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 151,216 control chromosomes in the GnomAD database, including 32,455 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 0.66 (32455 hom., cov: 33)
• Consequence: HLA-A ENST00000706904.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.528

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000706904.1	c.*1039C>T		3_prime_UTR_variant	9/9			A1
HLA-A	ENST00000706902.1	c.*953C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10
HLA-A	ENST00000706903.1	c.*269-44C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.659 AC: 99601 AN: 151094 Hom.: 32396 Cov.: 33

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.659 AC: 99713 AN: 151216 Hom.: 32455 Cov.: 33 AF XY: 0.659 AC XY: 48721 AN XY: 73916

Gnomad4 AFR AF: 0.714

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.689

Gnomad4 SAS AF: 0.629

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.611

Gnomad4 OTH AF: 0.678

Alfa AF: 0.664 Hom.: 6654

Asia WGS AF: 0.715 AC: 2485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	4.9
Dann	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs417162; hg19: chr6-29916505;