6-29942488-G-T

Position:

• chr6-29942488-G-T

Variant summary

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

The ENST00000706894(HLA-A):​c.-66G>T variant causes a 5 prime UTR 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 0.065 (848 hom., cov: 18)
  • Exomes 𝑓: 0.092 (10429 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A ENST00000706894 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.96

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]

ENSG00000227766 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2293C>A		intron_variant
HLA-A	NM_002116.8	c.-66G>T		upstream_gene_variant		ENST00000376809.10	NP_002107.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.-66G>T		upstream_gene_variant		6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 7782 AN: 120270 Hom.: 848 Cov.: 18

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0634

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0620

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0918 AC: 67988 AN: 740662 Hom.: 10429 Cov.: 10 AF XY: 0.0965 AC XY: 36537 AN XY: 378478

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0816

Gnomad4 EAS exome AF: 0.256

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0806

Gnomad4 OTH exome AF: 0.0943

GnomAD4 genome AF: 0.0646 AC: 7778 AN: 120354 Hom.: 848 Cov.: 18 AF XY: 0.0682 AC XY: 3945 AN XY: 57838

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0557

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0628

Alfa AF: 0.0208 Hom.: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.8
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41545520; hg19: chr6-29910265;