6-29945191-C-G

Position:

• chr6-29945191-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002116.8(HLA-A):​c.1046-43C>G 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 0.0012 (0 hom., cov: 10)
  • Exomes 𝑓: 0.0026 (26 hom.)
• Consequence: HLA-A NM_002116.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-A	NM_002116.8	c.1046-43C>G		intron_variant		ENST00000376809.10
LOC124901298	XR_007059541.1	n.403G>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-A	ENST00000376809.10	c.1046-43C>G		intron_variant			NM_002116.8	P3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 95 AN: 76444 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.000518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000651

Gnomad ASJ AF: 0.00567

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000929

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.00397

GnomAD3 exomes AF: 0.0489 AC: 12163 AN: 248502 Hom.: 443 AF XY: 0.0515 AC XY: 6911 AN XY: 134272

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0316

Gnomad SAS exome AF: 0.0633

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0509

Gnomad OTH exome AF: 0.0486

GnomAD4 exome AF: 0.00257 AC: 2282 AN: 889274 Hom.: 26 Cov.: 13 AF XY: 0.00277 AC XY: 1256 AN XY: 452940

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00408

Gnomad4 ASJ exome AF: 0.00967

Gnomad4 EAS exome AF: 0.00522

Gnomad4 SAS exome AF: 0.00592

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00124 AC: 95 AN: 76502 Hom.: 0 Cov.: 10 AF XY: 0.00122 AC XY: 45 AN XY: 36962

Gnomad4 AFR AF: 0.000517

Gnomad4 AMR AF: 0.000650

Gnomad4 ASJ AF: 0.00567

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.000927

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00167

Gnomad4 OTH AF: 0.00394

Alfa AF: 0.0496 Hom.: 214

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.7
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3823339; hg19: chr6-29912968;