6-29944050-G-A

Variant names:

• chr6-29944050-G-A
• rs9260168
• NM_002116.8:c.620-72G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):​c.620-72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0025 (1 hom., cov: 14)
  • Exomes 𝑓: 0.0061 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.506
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.620-72G>A		intron_variant	Intron 3 of 7	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.813+731C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.620-72G>A		intron_variant	Intron 3 of 7	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 187 AN: 78588 Hom.: 1 Cov.: 14

Gnomad AFR AF: 0.00221

Gnomad AMI AF: 0.00169

Gnomad AMR AF: 0.00394

Gnomad ASJ AF: 0.00420

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.00280

Gnomad FIN AF: 0.000992

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00199

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00611 AC: 6532 AN: 1069584 Hom.: 9 AF XY: 0.00697 AC XY: 3704 AN XY: 531488

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0130 AC: 282 AN: 21690

American (AMR) AF: 0.0271 AC: 714 AN: 26336

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 269 AN: 15392

East Asian (EAS) AF: 0.0113 AC: 208 AN: 18450

South Asian (SAS) AF: 0.0237 AC: 1428 AN: 60238

European-Finnish (FIN) AF: 0.00398 AC: 162 AN: 40740

Middle Eastern (MID) AF: 0.00792 AC: 33 AN: 4168

European-Non Finnish (NFE) AF: 0.00361 AC: 3035 AN: 840190

Other (OTH) AF: 0.00946 AC: 401 AN: 42380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00249 AC: 196 AN: 78612 Hom.: 1 Cov.: 14 AF XY: 0.00251 AC XY: 96 AN XY: 38270

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00231 AC: 42 AN: 18160

American (AMR) AF: 0.00411 AC: 25 AN: 6090

Ashkenazi Jewish (ASJ) AF: 0.00420 AC: 7 AN: 1666

East Asian (EAS) AF: 0.00756 AC: 19 AN: 2512

South Asian (SAS) AF: 0.00322 AC: 8 AN: 2484

European-Finnish (FIN) AF: 0.000992 AC: 6 AN: 6046

Middle Eastern (MID) AF: 0.00704 AC: 1 AN: 142

European-Non Finnish (NFE) AF: 0.00201 AC: 80 AN: 39896

Other (OTH) AF: 0.00684 AC: 7 AN: 1024

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.310 Hom.: 1626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.80
PhyloP100		-0.51
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: rs9260168; hg19: chr6-29911827; COSMIC: COSV65143335; COSMIC: COSV65143335;