6-29941979-G-C

Position:

• chr6-29941979-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000706894(HLA-A):​c.-268G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 148,454 control chromosomes in the GnomAD database, including 21,061 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 0.55 (21061 hom., cov: 33)
  • Exomes 𝑓: 0.63 (2522 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A ENST00000706894 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379

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]

HLA-A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2802C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000706894	c.-268G>C		5_prime_UTR_variant	1/8			ENSP00000516610.1
HLA-A	ENST00000706898	c.-268G>C		5_prime_UTR_variant	1/9			ENSP00000516611.1
HLA-A	ENST00000706904	c.-268G>C		5_prime_UTR_variant	1/9			ENSP00000516615.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 80926 AN: 148332 Hom.: 21013 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.554

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.627 AC: 7475 AN: 11926 Hom.: 2522 Cov.: 0 AF XY: 0.646 AC XY: 4342 AN XY: 6724

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.746

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.587

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.585

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.546 AC: 81025 AN: 148454 Hom.: 21061 Cov.: 33 AF XY: 0.544 AC XY: 39451 AN XY: 72476

Gnomad4 AFR AF: 0.592

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.580

Gnomad4 EAS AF: 0.496

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.550

Alfa AF: 0.404 Hom.: 620

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.59
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -13

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

Publications

LitVar

Other links and lift over

dbSNP: rs9260109; hg19: chr6-29909756;