6-32659875-C-G

Variant names:

• chr6-32659875-C-G
• rs4993986
• NM_002123.5:c.*361G>C

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.*361G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 150,970 control chromosomes in the GnomAD database, including 10,790 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 0.37 (10790 hom., cov: 28)
  • Exomes 𝑓: 0.076 (46 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 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.*361G>C		3_prime_UTR	Exon 5 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.*361G>C		3_prime_UTR	Exon 6 of 6	NP_001230890.1
	HLA-DQB1-AS1	NR_133907.1		n.-5C>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.*361G>C		3_prime_UTR	Exon 5 of 5	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.*361G>C		3_prime_UTR	Exon 6 of 6	ENSP00000364080.4
	HLA-DQB1	ENST00000487676.1	TSL:6	n.4236G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55679 AN: 150852 Hom.: 10779 Cov.: 28

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.374

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0764 AC: 1098 AN: 14376 Hom.: 46 Cov.: 0 AF XY: 0.0769 AC XY: 565 AN XY: 7348

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

African (AFR) AF: 0.0371 AC: 26 AN: 700

American (AMR) AF: 0.117 AC: 44 AN: 376

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 41 AN: 406

East Asian (EAS) AF: 0.0925 AC: 77 AN: 832

South Asian (SAS) AF: 0.0404 AC: 30 AN: 742

European-Finnish (FIN) AF: 0.0493 AC: 35 AN: 710

Middle Eastern (MID) AF: 0.0926 AC: 5 AN: 54

European-Non Finnish (NFE) AF: 0.0814 AC: 787 AN: 9674

Other (OTH) AF: 0.0601 AC: 53 AN: 882

⚠️ 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: 0.369 AC: 55728 AN: 150970 Hom.: 10790 Cov.: 28 AF XY: 0.372 AC XY: 27390 AN XY: 73694

African (AFR) AF: 0.303 AC: 12461 AN: 41110

American (AMR) AF: 0.492 AC: 7450 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3464

East Asian (EAS) AF: 0.521 AC: 2663 AN: 5114

South Asian (SAS) AF: 0.279 AC: 1322 AN: 4744

European-Finnish (FIN) AF: 0.390 AC: 4053 AN: 10388

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24829 AN: 67740

Other (OTH) AF: 0.373 AC: 778 AN: 2084

Alfa AF: 0.368 Hom.: 1296

Bravo AF: 0.381

Asia WGS AF: 0.371 AC: 1291 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.099
DANN	Benign	0.16
PhyloP100		-2.8
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: rs4993986; hg19: chr6-32627652;