rs76475517

Positions:

• chr6-29943768-G-A

Variant summary

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

The NM_002116.8(HLA-A):​c.619+225G>A variant causes a intron 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 0.011 (14 hom., cov: 11)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250

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]

LOC124901298 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.619+225G>A		intron_variant		ENST00000376809.10
LOC124901298	XR_007059541.1	n.813+1013C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.619+225G>A		intron_variant			NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 779 AN: 74740 Hom.: 11 Cov.: 11

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00766

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.0238

Gnomad SAS AF: 0.0179

Gnomad FIN AF: 0.00883

Gnomad MID AF: 0.00617

Gnomad NFE AF: 0.00996

Gnomad OTH AF: 0.0160

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 786 AN: 74766 Hom.: 14 Cov.: 11 AF XY: 0.0101 AC XY: 365 AN XY: 36154

Gnomad4 AFR AF: 0.00856

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.0179

Gnomad4 FIN AF: 0.00883

Gnomad4 NFE AF: 0.00996

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0995 Hom.: 169

Asia WGS AF: 0.271 AC: 942 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.89

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: rs76475517; hg19: chr6-29911545;