rs41545520

Positions:

• chr6-29942488-G-A
• chr6-29942488-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000429656.1(ENSG00000227766):​n.580C>T 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 0.11 (9 hom., cov: 18)
  • Exomes 𝑓: 0.070 (497 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENST00000429656.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.96

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC124901298	XR_007059541.1	n.813+2293C>T		intron_variant, non_coding_transcript_variant
HLA-A	NM_002116.8			upstream_gene_variant		ENST00000376809.10	NP_002107.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000429656.1	n.580C>T		non_coding_transcript_exon_variant	1/1
HLA-A	ENST00000376809.10			upstream_gene_variant			NM_002116.8	ENSP00000366005	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13395 AN: 116976 Hom.: 9 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0106

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0697 AC: 50473 AN: 724586 Hom.: 497 Cov.: 10 AF XY: 0.0711 AC XY: 26329 AN XY: 370134

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.0330

Gnomad4 NFE exome AF: 0.0474

Gnomad4 OTH exome AF: 0.0933

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.115 AC: 13425 AN: 117062 Hom.: 9 Cov.: 18 AF XY: 0.115 AC XY: 6457 AN XY: 56282

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0586

Gnomad4 OTH AF: 0.131

Alfa AF: 0.00989 Hom.: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.5
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs41545520; hg19: chr6-29910265;