rs2735113

Positions:

• chr6-29942390-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000429656.1(ENSG00000227766):​n.678G>C variant causes a non coding transcript exon 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: ENST00000429656.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285

Genes affected

(HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2391G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000429656.1	n.678G>C		non_coding_transcript_exon_variant	1/1

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

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.0335

Gnomad4 ASJ exome AF: 0.0350

Gnomad4 EAS exome AF: 0.00223

Gnomad4 SAS exome AF: 0.0324

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0317

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0817

Gnomad4 ASJ AF: 0.0771

Gnomad4 EAS AF: 0.0151

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0712

Gnomad4 OTH AF: 0.0865

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2735113; hg19: chr6-29910167;