rs2735113

Variant names:

• chr6-29942390-C-G
• rs2735113
• ENST00000376806.9:c.-164C>G

Variant summary

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

The ENST00000376806.9(HLA-A):​c.-164C>G variant causes a 5 prime UTR premature start codon gain 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 0.076 (502 hom., cov: 20)
  • Exomes 𝑓: 0.027 (417 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A ENST00000376806.9 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285
• 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]

ENSG00000227766 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2391G>C		intron_variant	Intron 1 of 2
HLA-A	NM_002116.8	c.-164C>G		upstream_gene_variant		ENST00000376809.10	NP_002107.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.-164C>G		upstream_gene_variant		6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.0761 AC: 9916 AN: 130300 Hom.: 498 Cov.: 20

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0885

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.0771

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0434

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0719

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0869

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0266 AC: 8580 AN: 322686 Hom.: 417 Cov.: 4 AF XY: 0.0266 AC XY: 4565 AN XY: 171706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0481 AC: 376 AN: 7820

American (AMR) AF: 0.0335 AC: 303 AN: 9032

Ashkenazi Jewish (ASJ) AF: 0.0350 AC: 303 AN: 8660

East Asian (EAS) AF: 0.00223 AC: 36 AN: 16148

South Asian (SAS) AF: 0.0324 AC: 1074 AN: 33186

European-Finnish (FIN) AF: 0.0143 AC: 291 AN: 20360

Middle Eastern (MID) AF: 0.0323 AC: 58 AN: 1796

European-Non Finnish (NFE) AF: 0.0268 AC: 5561 AN: 207468

Other (OTH) AF: 0.0317 AC: 578 AN: 18216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0762 AC: 9939 AN: 130392 Hom.: 502 Cov.: 20 AF XY: 0.0751 AC XY: 4739 AN XY: 63114

African (AFR) AF: 0.101 AC: 3501 AN: 34676

American (AMR) AF: 0.0817 AC: 988 AN: 12088

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 238 AN: 3086

East Asian (EAS) AF: 0.0151 AC: 67 AN: 4448

South Asian (SAS) AF: 0.0435 AC: 179 AN: 4118

European-Finnish (FIN) AF: 0.0483 AC: 418 AN: 8654

Middle Eastern (MID) AF: 0.0741 AC: 20 AN: 270

European-Non Finnish (NFE) AF: 0.0712 AC: 4303 AN: 60470

Other (OTH) AF: 0.0865 AC: 153 AN: 1768

Alfa AF: 0.0714 Hom.: 49

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.56
PhyloP100		-0.28
PromoterAI		-0.0079	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2735113; hg19: chr6-29910167;