6-32659937-T-G

Variant names:

• chr6-32659937-T-G
• rs1063355
• NM_002123.5:c.*299A>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.*299A>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 0.566 in 149,022 control chromosomes in the GnomAD database, including 24,323 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 0.57 (24323 hom., cov: 27)
  • Exomes 𝑓: 0.13 (484 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 119 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.64 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.*299A>C		3_prime_UTR	Exon 5 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.*299A>C		3_prime_UTR	Exon 6 of 6	NP_001230890.1	Q5SU54
	HLA-DQB1-AS1	NR_133907.1		n.58T>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.*299A>C		3_prime_UTR	Exon 5 of 5	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.*299A>C		3_prime_UTR	Exon 6 of 6	ENSP00000364080.4	Q5SU54
	HLA-DQB1	ENST00000399084.5	TSL:6	c.*299A>C		3_prime_UTR	Exon 6 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 84311 AN: 148906 Hom.: 24315 Cov.: 27

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.708

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.584

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.130 AC: 7236 AN: 55750 Hom.: 484 Cov.: 0 AF XY: 0.131 AC XY: 3731 AN XY: 28566

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

African (AFR) AF: 0.0960 AC: 233 AN: 2426

American (AMR) AF: 0.174 AC: 218 AN: 1252

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 298 AN: 1640

East Asian (EAS) AF: 0.115 AC: 474 AN: 4110

South Asian (SAS) AF: 0.0821 AC: 193 AN: 2350

European-Finnish (FIN) AF: 0.0909 AC: 373 AN: 4102

Middle Eastern (MID) AF: 0.220 AC: 48 AN: 218

European-Non Finnish (NFE) AF: 0.137 AC: 4925 AN: 36070

Other (OTH) AF: 0.132 AC: 474 AN: 3582

⚠️ 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: 0.566 AC: 84365 AN: 149022 Hom.: 24323 Cov.: 27 AF XY: 0.563 AC XY: 40904 AN XY: 72716

African (AFR) AF: 0.512 AC: 20622 AN: 40302

American (AMR) AF: 0.651 AC: 9755 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2159 AN: 3442

East Asian (EAS) AF: 0.607 AC: 3106 AN: 5118

South Asian (SAS) AF: 0.502 AC: 2341 AN: 4664

European-Finnish (FIN) AF: 0.509 AC: 5204 AN: 10220

Middle Eastern (MID) AF: 0.700 AC: 203 AN: 290

European-Non Finnish (NFE) AF: 0.585 AC: 39231 AN: 67018

Other (OTH) AF: 0.580 AC: 1203 AN: 2074

Alfa AF: 0.583 Hom.: 45585

Bravo AF: 0.584

Asia WGS AF: 0.486 AC: 1692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.61
PhyloP100		-0.42
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: rs1063355; hg19: chr6-32627714;