6-32661360-T-G

Variant names:

• chr6-32661360-T-G
• rs1140343
• NM_002123.5:c.759A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002123.5(HLA-DQB1):​c.759A>C​(p.Gln253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,057,032 control chromosomes in the GnomAD database, including 169,105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (17966 hom., cov: 20)
  • Exomes 𝑓: 0.49 (151139 hom.)
• Consequence: HLA-DQB1 NM_002123.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011523664).
• BS2: High Homozygotes in GnomAd4 at 17966 AR gene

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.759A>C	p.Gln253His	missense	Exon 4 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.759A>C	p.Gln253His	missense	Exon 4 of 6	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.759A>C	p.Gln253His	missense	Exon 4 of 5	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.759A>C	p.Gln253His	missense	Exon 4 of 6	ENSP00000364080.4
	HLA-DQB1	ENST00000399084.5	TSL:6	c.759A>C	p.Gln253His	missense	Exon 5 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 61557 AN: 121302 Hom.: 17962 Cov.: 20

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.679

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.204 AC: 27126 AN: 133128 AF XY: 0.212

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.0961

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.488 AC: 456721 AN: 935656 Hom.: 151139 Cov.: 25 AF XY: 0.488 AC XY: 230231 AN XY: 471482

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

African (AFR) AF: 0.419 AC: 9961 AN: 23750

American (AMR) AF: 0.706 AC: 20566 AN: 29126

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 9673 AN: 17426

East Asian (EAS) AF: 0.429 AC: 9847 AN: 22968

South Asian (SAS) AF: 0.470 AC: 31590 AN: 67162

European-Finnish (FIN) AF: 0.398 AC: 14042 AN: 35304

Middle Eastern (MID) AF: 0.523 AC: 1572 AN: 3008

European-Non Finnish (NFE) AF: 0.488 AC: 339789 AN: 696580

Other (OTH) AF: 0.488 AC: 19681 AN: 40332

⚠️ 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: 0.507 AC: 61584 AN: 121376 Hom.: 17966 Cov.: 20 AF XY: 0.498 AC XY: 29096 AN XY: 58440

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

African (AFR) AF: 0.465 AC: 16090 AN: 34616

American (AMR) AF: 0.559 AC: 5965 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1509 AN: 2660

East Asian (EAS) AF: 0.511 AC: 1831 AN: 3582

South Asian (SAS) AF: 0.435 AC: 1609 AN: 3700

European-Finnish (FIN) AF: 0.385 AC: 2867 AN: 7438

Middle Eastern (MID) AF: 0.675 AC: 166 AN: 246

European-Non Finnish (NFE) AF: 0.540 AC: 30334 AN: 56142

Other (OTH) AF: 0.531 AC: 881 AN: 1660

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.578 Hom.: 48656

ExAC AF: 0.245 AC: 23958

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.043
DANN	Benign	0.78
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.25
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.26		Loss of sheet (P = 0.0817)
MPC		0.52
ClinPred		0.00067	T
GERP RS		1.9
gMVP		0.26
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: rs1140343; hg19: chr6-32629137; COSMIC: COSV66569175; COSMIC: COSV66569175;