chr6-29941898-G-T

Variant names:

• chr6-29941898-G-T
• rs9260105
• ENST00000396634.5:c.-281-68G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000396634.5(HLA-A):​c.-281-68G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 169,394 control chromosomes in the GnomAD database, including 200 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 0.045 (177 hom., cov: 35)
  • Exomes 𝑓: 0.035 (23 hom.)
• Consequence: HLA-A ENST00000396634.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2883C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000396634.5	c.-281-68G>T		intron_variant	Intron 1 of 9	6		ENSP00000379873.1
POLR1HASP	ENST00000849679.1	n.66-13352C>A		intron_variant	Intron 1 of 5
POLR1HASP	ENST00000849682.1	n.751-13352C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6854 AN: 152118 Hom.: 176 Cov.: 35

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0402

GnomAD4 exome AF: 0.0346 AC: 594 AN: 17158 Hom.: 23 AF XY: 0.0375 AC XY: 393 AN XY: 10486

African (AFR) AF: 0.0685 AC: 20 AN: 292

American (AMR) AF: 0.0183 AC: 12 AN: 654

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 7 AN: 418

East Asian (EAS) AF: 0.00185 AC: 1 AN: 540

South Asian (SAS) AF: 0.0346 AC: 178 AN: 5142

European-Finnish (FIN) AF: 0.0277 AC: 15 AN: 542

Middle Eastern (MID) AF: 0.0556 AC: 5 AN: 90

European-Non Finnish (NFE) AF: 0.0388 AC: 331 AN: 8534

Other (OTH) AF: 0.0264 AC: 25 AN: 946

GnomAD4 genome AF: 0.0451 AC: 6866 AN: 152236 Hom.: 177 Cov.: 35 AF XY: 0.0452 AC XY: 3361 AN XY: 74434

African (AFR) AF: 0.0707 AC: 2937 AN: 41528

American (AMR) AF: 0.0325 AC: 497 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5188

South Asian (SAS) AF: 0.0352 AC: 170 AN: 4830

European-Finnish (FIN) AF: 0.0411 AC: 435 AN: 10594

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2556 AN: 68012

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0430 Hom.: 17

Bravo AF: 0.0464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.74
PhyloP100		-0.068
PromoterAI		0.0079	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9260105; hg19: chr6-29909675;