6-29945290-T-C

Variant names:

• chr6-29945290-T-C
• rs3823342
• NM_002116.8:c.1093+9T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002116.8(HLA-A):​c.1093+9T>C 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 0.37 (5969 hom., cov: 11)
  • Exomes 𝑓: 0.30 (53213 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 28 publications found

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]

POLR1HASP (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.1093+9T>C		intron_variant	Intron 7 of 7	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.304A>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.1093+9T>C		intron_variant	Intron 7 of 7	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.365 AC: 25736 AN: 70498 Hom.: 5940 Cov.: 11

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.438

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.531 AC: 128321 AN: 241530 AF XY: 0.524

Gnomad AFR exome AF: 0.585

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.299 AC: 195621 AN: 653572 Hom.: 53213 Cov.: 11 AF XY: 0.306 AC XY: 103262 AN XY: 337954

African (AFR) AF: 0.427 AC: 7476 AN: 17508

American (AMR) AF: 0.563 AC: 16532 AN: 29342

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 6033 AN: 14482

East Asian (EAS) AF: 0.519 AC: 14623 AN: 28192

South Asian (SAS) AF: 0.380 AC: 20729 AN: 54580

European-Finnish (FIN) AF: 0.286 AC: 9194 AN: 32168

Middle Eastern (MID) AF: 0.310 AC: 923 AN: 2982

European-Non Finnish (NFE) AF: 0.246 AC: 109401 AN: 443930

Other (OTH) AF: 0.352 AC: 10710 AN: 30388

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.365 AC: 25789 AN: 70564 Hom.: 5969 Cov.: 11 AF XY: 0.355 AC XY: 11965 AN XY: 33696

African (AFR) AF: 0.478 AC: 9846 AN: 20580

American (AMR) AF: 0.466 AC: 2990 AN: 6412

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 689 AN: 1634

East Asian (EAS) AF: 0.415 AC: 1228 AN: 2956

South Asian (SAS) AF: 0.370 AC: 864 AN: 2336

European-Finnish (FIN) AF: 0.187 AC: 793 AN: 4242

Middle Eastern (MID) AF: 0.437 AC: 76 AN: 174

European-Non Finnish (NFE) AF: 0.287 AC: 8845 AN: 30856

Other (OTH) AF: 0.388 AC: 375 AN: 966

Alfa AF: 0.499 Hom.: 16290

Asia WGS AF: 0.464 AC: 1612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.46
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3823342; hg19: chr6-29913067; COSMIC: COSV65136582;