chr6-29941898-G-T

Position:

• chr6-29941898-G-T

Variant summary

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

The XR_007059541.1(LOC124901298):​n.813+2883C>A variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 169,394 control chromosomes in the GnomAD database, including 200 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 0.045 (177 hom., cov: 35)
  • Exomes 𝑓: 0.035 (23 hom.)
• Consequence: LOC124901298 XR_007059541.1 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680

Genes affected

LOC124901298 (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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124901298	XR_007059541.1	n.813+2883C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000396634.5	c.-281-68G>T		intron_variant				P3

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6854 AN: 152118 Hom.: 176 Cov.: 35

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0402

GnomAD4 exome AF: 0.0346 AC: 594 AN: 17158 Hom.: 23 AF XY: 0.0375 AC XY: 393 AN XY: 10486

Gnomad4 AFR exome AF: 0.0685

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.00185

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0451 AC: 6866 AN: 152236 Hom.: 177 Cov.: 35 AF XY: 0.0452 AC XY: 3361 AN XY: 74434

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.0376

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0430 Hom.: 17

Bravo AF: 0.0464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.74

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: rs9260105; hg19: chr6-29909675;