rs9260100

Variant names:

• chr6-29941765-A-G
• rs9260100
• ENST00000396634.5:c.-281-201A>G

Variant summary

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

The ENST00000396634.5(HLA-A):​c.-281-201A>G 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 151,258 control chromosomes in the GnomAD database, including 496 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 (496 hom., cov: 34)
• Consequence: HLA-A ENST00000396634.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• 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]

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

POLR1HASP (HGNC:):

ACMG classification

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

• 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.-281-201A>G		intron	N/A	ENSP00000379873.1	P04439-1
	POLR1HASP	ENST00000849679.1		n.66-13219T>C		intron	N/A
	POLR1HASP	ENST00000849682.1		n.751-13219T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19565 AN: 151138 Hom.: 492 Cov.: 34

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0890

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.144

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

GnomAD4 genome AF: 0.130 AC: 19613 AN: 151258 Hom.: 496 Cov.: 34 AF XY: 0.129 AC XY: 9575 AN XY: 73970

African (AFR) AF: 0.171 AC: 7014 AN: 41022

American (AMR) AF: 0.144 AC: 2184 AN: 15200

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

East Asian (EAS) AF: 0.122 AC: 625 AN: 5120

South Asian (SAS) AF: 0.163 AC: 777 AN: 4762

European-Finnish (FIN) AF: 0.0890 AC: 942 AN: 10584

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7193 AN: 67816

Other (OTH) AF: 0.143 AC: 300 AN: 2098

Alfa AF: 0.115 Hom.: 48

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.74
PhyloP100		-0.50
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9260100;

hg19: chr6-29909542;

COSMIC: COSV65139499;

COSMIC: COSV65139499;