6-29941979-G-T

Variant names:

• chr6-29941979-G-T
• rs9260109
• ENST00000706894.1:c.-268G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000706894.1(HLA-A):​c.-268G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 148,904 control chromosomes in the GnomAD database, including 1,283 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 0.13 (1283 hom., cov: 33)
  • Exomes 𝑓: 0.11 (114 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A ENST00000706894.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379
• Publications: 2 publications found

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]

POLR1HASP (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2802C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000706894.1	c.-268G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8			ENSP00000516610.1
HLA-A	ENST00000706898.1	c.-268G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9			ENSP00000516611.1
HLA-A	ENST00000706904.1	c.-268G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9			ENSP00000516615.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 18980 AN: 148786 Hom.: 1278 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0973

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.137

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.112 AC: 1331 AN: 11882 Hom.: 114 Cov.: 0 AF XY: 0.114 AC XY: 761 AN XY: 6700

African (AFR) AF: 0.107 AC: 27 AN: 252

American (AMR) AF: 0.0966 AC: 34 AN: 352

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 34 AN: 442

East Asian (EAS) AF: 0.270 AC: 192 AN: 712

South Asian (SAS) AF: 0.119 AC: 325 AN: 2742

European-Finnish (FIN) AF: 0.0893 AC: 20 AN: 224

Middle Eastern (MID) AF: 0.125 AC: 11 AN: 88

European-Non Finnish (NFE) AF: 0.0966 AC: 615 AN: 6364

Other (OTH) AF: 0.103 AC: 73 AN: 706

GnomAD4 genome AF: 0.128 AC: 18992 AN: 148904 Hom.: 1283 Cov.: 33 AF XY: 0.129 AC XY: 9403 AN XY: 72710

African (AFR) AF: 0.134 AC: 5471 AN: 40860

American (AMR) AF: 0.176 AC: 2651 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 443 AN: 3416

East Asian (EAS) AF: 0.218 AC: 1084 AN: 4964

South Asian (SAS) AF: 0.167 AC: 758 AN: 4528

European-Finnish (FIN) AF: 0.0973 AC: 1017 AN: 10454

Middle Eastern (MID) AF: 0.153 AC: 44 AN: 288

European-Non Finnish (NFE) AF: 0.107 AC: 7133 AN: 66378

Other (OTH) AF: 0.144 AC: 297 AN: 2058

Alfa AF: 0.0785 Hom.: 620

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.60
PhyloP100		-0.38
PromoterAI		-0.082	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -13

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

Other links and lift over

dbSNP: rs9260109; hg19: chr6-29909756;