6-32666690-C-T

Variant names:

• chr6-32666690-C-T
• rs3891175
• ENST00000399084.5:c.-63-20G>A

Variant summary

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

The ENST00000399084.5(HLA-DQB1):​c.-63-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 581,916 control chromosomes in the GnomAD database, including 5,839 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 0.20 (3147 hom., cov: 28)
  • Exomes 𝑓: 0.074 (2692 hom.)
• Consequence: HLA-DQB1 ENST00000399084.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.804
• Publications: 44 publications found

Genes affected

HLA-DQB1 (HGNC:4944): (major histocompatibility complex, class II, DQ beta 1) HLA-DQB1 belongs to the HLA class II beta chain paralogs. This 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 beta chain is approximately 26-28 kDa and it contains six exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5	c.-83G>A		upstream_gene_variant		ENST00000434651.7	NP_002114.3
HLA-DQB1	NM_001243961.2	c.-83G>A		upstream_gene_variant			NP_001230890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7	c.-83G>A		upstream_gene_variant		6	NM_002123.5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	c.-83G>A		upstream_gene_variant		6		ENSP00000364080.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29534 AN: 150792 Hom.: 3145 Cov.: 28

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0816

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.0740 AC: 31916 AN: 431008 Hom.: 2692 Cov.: 5 AF XY: 0.0777 AC XY: 18148 AN XY: 233650

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

African (AFR) AF: 0.0587 AC: 642 AN: 10944

American (AMR) AF: 0.0397 AC: 606 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 871 AN: 13514

East Asian (EAS) AF: 0.0103 AC: 249 AN: 24140

South Asian (SAS) AF: 0.136 AC: 5598 AN: 41306

European-Finnish (FIN) AF: 0.0466 AC: 1688 AN: 36196

Middle Eastern (MID) AF: 0.194 AC: 621 AN: 3202

European-Non Finnish (NFE) AF: 0.0759 AC: 19996 AN: 263454

Other (OTH) AF: 0.0716 AC: 1645 AN: 22988

⚠️ 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: 0.196 AC: 29539 AN: 150908 Hom.: 3147 Cov.: 28 AF XY: 0.190 AC XY: 13990 AN XY: 73720

African (AFR) AF: 0.209 AC: 8598 AN: 41080

American (AMR) AF: 0.157 AC: 2384 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3460

East Asian (EAS) AF: 0.0818 AC: 421 AN: 5148

South Asian (SAS) AF: 0.227 AC: 1078 AN: 4748

European-Finnish (FIN) AF: 0.121 AC: 1267 AN: 10472

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14632 AN: 67540

Other (OTH) AF: 0.201 AC: 419 AN: 2082

Alfa AF: 0.215 Hom.: 9226

Bravo AF: 0.203

Asia WGS AF: 0.115 AC: 401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.88
PhyloP100		-0.80
PromoterAI		-0.0038	Neutral
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: rs3891175; hg19: chr6-32634467; COSMIC: COSV66571800; COSMIC: COSV66571800;