6-32660651-C-A

Variant names:

• chr6-32660651-C-A
• rs2854275
• NM_002123.5:c.773-402G>T

Variant summary

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

The NM_002123.5(HLA-DQB1):​c.773-402G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 146,342 control chromosomes in the GnomAD database, including 880 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 0.096 (880 hom., cov: 25)
  • Exomes 𝑓: 0.080 (1615 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388
• Publications: 86 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]

HLA-DQB1-AS1 (HGNC:39762): (HLA-DQB1 antisense RNA 1)

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 (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002123.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	NM_002123.5	MANE Select	c.773-402G>T		intron	N/A	NP_002114.3
	HLA-DQB1-AS1	NR_133907.1		n.474C>A		non_coding_transcript_exon	Exon 2 of 2
	HLA-DQB1	NM_001243961.2		c.796+208G>T		intron	N/A	NP_001230890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.773-402G>T		intron	N/A	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.796+208G>T		intron	N/A	ENSP00000364080.4
	HLA-DQB1-AS1	ENST00000419852.1	TSL:6	n.474C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0963 AC: 14081 AN: 146224 Hom.: 879 Cov.: 25

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.0590

Gnomad AMR AF: 0.0673

Gnomad ASJ AF: 0.0583

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0864

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.0889

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0796 AC: 21885 AN: 274896 Hom.: 1615 Cov.: 2 AF XY: 0.0830 AC XY: 12145 AN XY: 146364

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

African (AFR) AF: 0.0537 AC: 506 AN: 9426

American (AMR) AF: 0.0512 AC: 552 AN: 10784

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 350 AN: 7888

East Asian (EAS) AF: 0.0254 AC: 407 AN: 16032

South Asian (SAS) AF: 0.123 AC: 3565 AN: 29092

European-Finnish (FIN) AF: 0.0614 AC: 1077 AN: 17544

Middle Eastern (MID) AF: 0.0543 AC: 65 AN: 1196

European-Non Finnish (NFE) AF: 0.0853 AC: 14254 AN: 167084

Other (OTH) AF: 0.0700 AC: 1109 AN: 15850

⚠️ 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: 0.0963 AC: 14087 AN: 146342 Hom.: 880 Cov.: 25 AF XY: 0.0939 AC XY: 6685 AN XY: 71222

African (AFR) AF: 0.0687 AC: 2777 AN: 40404

American (AMR) AF: 0.0671 AC: 941 AN: 14024

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 195 AN: 3346

East Asian (EAS) AF: 0.0516 AC: 244 AN: 4730

South Asian (SAS) AF: 0.119 AC: 547 AN: 4604

European-Finnish (FIN) AF: 0.0864 AC: 849 AN: 9830

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.125 AC: 8270 AN: 66228

Other (OTH) AF: 0.0879 AC: 179 AN: 2036

Alfa AF: 0.122 Hom.: 3069

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.76
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: rs2854275; hg19: chr6-32628428;