ENST00000460633.1:n.2252A>G

Variant names:

• chr6-32643864-A-G
• rs9273012
• ENST00000460633.1:n.2252A>G

Variant summary

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

The ENST00000460633.1(HLA-DQA1):​n.2252A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 150,892 control chromosomes in the GnomAD database, including 6,798 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 0.29 (6798 hom., cov: 27)
  • Exomes 𝑓: 0.033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 ENST00000460633.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 50 publications found

Genes affected

HLA-DQA1 (HGNC:4942): (major histocompatibility complex, class II, DQ alpha 1) HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B Lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa. It is encoded by 5 exons; exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	XM_006715079.5	c.613+1611A>G		intron_variant	Intron 3 of 3		XP_006715142.1
HLA-DQA1	NM_002122.5	c.*933A>G		downstream_gene_variant		ENST00000343139.11	NP_002113.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000460633.1	n.2252A>G		non_coding_transcript_exon_variant	Exon 3 of 3	6
HLA-DQA1	ENST00000343139.11	c.*933A>G		downstream_gene_variant		6	NM_002122.5	ENSP00000339398.5
HLA-DQA1	ENST00000395363.5	c.*592A>G		downstream_gene_variant		6		ENSP00000378767.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 43934 AN: 150774 Hom.: 6796 Cov.: 27

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.310

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0326 AC: 3 AN: 92 Hom.: 0 Cov.: 0 AF XY: 0.0484 AC XY: 3 AN XY: 62

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0349 AC: 3 AN: 86

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.062893), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.291 AC: 43959 AN: 150892 Hom.: 6798 Cov.: 27 AF XY: 0.291 AC XY: 21395 AN XY: 73642

African (AFR) AF: 0.307 AC: 12618 AN: 41074

American (AMR) AF: 0.325 AC: 4908 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1027 AN: 3462

East Asian (EAS) AF: 0.255 AC: 1306 AN: 5128

South Asian (SAS) AF: 0.250 AC: 1185 AN: 4744

European-Finnish (FIN) AF: 0.273 AC: 2838 AN: 10400

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19130 AN: 67686

Other (OTH) AF: 0.308 AC: 646 AN: 2096

Alfa AF: 0.298 Hom.: 18811

Bravo AF: 0.297

Asia WGS AF: 0.253 AC: 878 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	1.5
DANN	Benign	0.31
PhyloP100		-0.066

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9273012; hg19: chr6-32611641;