6-32666786-C-T

Variant names:

• chr6-32666786-C-T
• rs78202368
• ENST00000399084.5:c.-63-116G>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.-63-116G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 211,278 control chromosomes in the GnomAD database, including 1,033 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 0.22 (958 hom., cov: 8)
  • Exomes 𝑓: 0.023 (75 hom.)
• Consequence: HLA-DQB1 ENST00000399084.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.13
• Publications: 8 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399084.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	NM_002123.5	MANE Select	c.-179G>A		upstream_gene	N/A	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.-179G>A		upstream_gene	N/A	NP_001230890.1	Q5SU54

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000399084.5	TSL:6	c.-63-116G>A		intron	N/A	ENSP00000382034.1
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.-179G>A		upstream_gene	N/A	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.-179G>A		upstream_gene	N/A	ENSP00000364080.4	Q5SU54

Frequencies

GnomAD3 genomes AF: 0.216 AC: 15164 AN: 70280 Hom.: 958 Cov.: 8

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.0234 AC: 3294 AN: 140942 Hom.: 75 AF XY: 0.0241 AC XY: 1796 AN XY: 74446

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

African (AFR) AF: 0.0205 AC: 77 AN: 3760

American (AMR) AF: 0.00996 AC: 31 AN: 3114

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 39 AN: 3560

East Asian (EAS) AF: 0.00159 AC: 14 AN: 8786

South Asian (SAS) AF: 0.0364 AC: 425 AN: 11666

European-Finnish (FIN) AF: 0.0110 AC: 148 AN: 13468

Middle Eastern (MID) AF: 0.0710 AC: 50 AN: 704

European-Non Finnish (NFE) AF: 0.0262 AC: 2295 AN: 87606

Other (OTH) AF: 0.0260 AC: 215 AN: 8278

⚠️ 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: 0.216 AC: 15169 AN: 70336 Hom.: 958 Cov.: 8 AF XY: 0.207 AC XY: 7117 AN XY: 34406

African (AFR) AF: 0.217 AC: 4302 AN: 19828

American (AMR) AF: 0.179 AC: 997 AN: 5568

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 187 AN: 1112

East Asian (EAS) AF: 0.0983 AC: 226 AN: 2298

South Asian (SAS) AF: 0.200 AC: 505 AN: 2522

European-Finnish (FIN) AF: 0.150 AC: 749 AN: 4980

Middle Eastern (MID) AF: 0.321 AC: 34 AN: 106

European-Non Finnish (NFE) AF: 0.243 AC: 7932 AN: 32684

Other (OTH) AF: 0.207 AC: 185 AN: 892

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		-2.1
PromoterAI		-0.23	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs78202368; hg19: chr6-32634563;