6-32662025-A-G

Variant names:

• chr6-32662025-A-G
• rs1049092
• NM_002123.5:c.603T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002123.5(HLA-DQB1):​c.603T>C​(p.Asp201Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,277,456 control chromosomes in the GnomAD database, including 250,456 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 0.55 (21923 hom., cov: 23)
  • Exomes 𝑓: 0.58 (228533 hom.)
• Consequence: HLA-DQB1 NM_002123.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 25 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	NM_002123.5	MANE Select	c.603T>C	p.Asp201Asp	synonymous	Exon 3 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.603T>C	p.Asp201Asp	synonymous	Exon 3 of 6	NP_001230890.1	Q5SU54

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.603T>C	p.Asp201Asp	synonymous	Exon 3 of 5	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.603T>C	p.Asp201Asp	synonymous	Exon 3 of 6	ENSP00000364080.4	Q5SU54
	HLA-DQB1	ENST00000399084.5	TSL:6	c.603T>C	p.Asp201Asp	synonymous	Exon 4 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 73641 AN: 133706 Hom.: 21923 Cov.: 23

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.735

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.573

GnomAD2 exomes AF: 0.622 AC: 144698 AN: 232662 AF XY: 0.623

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.731

Gnomad FIN exome AF: 0.508

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.576 AC: 658676 AN: 1143664 Hom.: 228533 Cov.: 34 AF XY: 0.579 AC XY: 332981 AN XY: 574962

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

African (AFR) AF: 0.438 AC: 11965 AN: 27338

American (AMR) AF: 0.720 AC: 22256 AN: 30894

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 13047 AN: 20114

East Asian (EAS) AF: 0.739 AC: 23721 AN: 32092

South Asian (SAS) AF: 0.656 AC: 49347 AN: 75240

European-Finnish (FIN) AF: 0.466 AC: 19377 AN: 41614

Middle Eastern (MID) AF: 0.674 AC: 3305 AN: 4902

European-Non Finnish (NFE) AF: 0.565 AC: 487875 AN: 862946

Other (OTH) AF: 0.573 AC: 27783 AN: 48524

⚠️ 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: 0.551 AC: 73674 AN: 133792 Hom.: 21923 Cov.: 23 AF XY: 0.548 AC XY: 35353 AN XY: 64558

African (AFR) AF: 0.476 AC: 17609 AN: 37016

American (AMR) AF: 0.615 AC: 7578 AN: 12328

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2092 AN: 3158

East Asian (EAS) AF: 0.704 AC: 2835 AN: 4028

South Asian (SAS) AF: 0.641 AC: 2723 AN: 4246

European-Finnish (FIN) AF: 0.447 AC: 3770 AN: 8426

Middle Eastern (MID) AF: 0.728 AC: 198 AN: 272

European-Non Finnish (NFE) AF: 0.574 AC: 35414 AN: 61722

Other (OTH) AF: 0.571 AC: 1067 AN: 1868

Alfa AF: 0.593 Hom.: 7217

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.36
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1049092; hg19: chr6-32629802;