ENST00000396634.5:c.-281-181C>A

Variant names:

• chr6-29941785-C-A
• rs9260102
• ENST00000396634.5:c.-281-181C>A

Variant summary

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

The ENST00000396634.5(HLA-A):​c.-281-181C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 151,232 control chromosomes in the GnomAD database, including 493 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 (493 hom., cov: 35)
• Consequence: HLA-A ENST00000396634.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.724
• Publications: 4 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]

HCG4P5 (HGNC:22925): (HLA complex group 4 pseudogene 5)

POLR1HASP (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396634.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	ENST00000396634.5	TSL:6	c.-281-181C>A		intron	N/A	ENSP00000379873.1	P04439-1
	POLR1HASP	ENST00000849679.1		n.66-13239G>T		intron	N/A
	POLR1HASP	ENST00000849682.1		n.751-13239G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19584 AN: 151116 Hom.: 489 Cov.: 35

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0892

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.130 AC: 19630 AN: 151232 Hom.: 493 Cov.: 35 AF XY: 0.130 AC XY: 9585 AN XY: 73928

African (AFR) AF: 0.171 AC: 7027 AN: 41010

American (AMR) AF: 0.144 AC: 2184 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 442 AN: 3454

East Asian (EAS) AF: 0.122 AC: 630 AN: 5144

South Asian (SAS) AF: 0.163 AC: 773 AN: 4750

European-Finnish (FIN) AF: 0.0892 AC: 943 AN: 10568

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7192 AN: 67814

Other (OTH) AF: 0.144 AC: 302 AN: 2100

Alfa AF: 0.115 Hom.: 49

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		-0.72
PromoterAI		0.18	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9260102; hg19: chr6-29909562;