Genetic Variant NM_002123.5:c.260G>T (chr6-32664917-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002123.5(HLA-DQB1):c.260G>T(p.Arg87Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.000063 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQB1
NM_002123.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.297

Publications

25 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003316313).

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.260G>T	p.Arg87Leu	missense	Exon 2 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.260G>T	p.Arg87Leu	missense	Exon 2 of 6	NP_001230890.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.260G>T	p.Arg87Leu	missense	Exon 2 of 5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	TSL:6	c.260G>T	p.Arg87Leu	missense	Exon 2 of 6	ENSP00000364080.4
HLA-DQB1	ENST00000399084.5	TSL:6	c.260G>T	p.Arg87Leu	missense	Exon 3 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes

AF:

0.0000632

AC:

AN:

126488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000972

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000695

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00670

AC:

1046

AN:

156124

AF XY:

0.00799

show subpopulations

Gnomad AFR exome

AF:

0.00238

Gnomad AMR exome

AF:

0.00201

Gnomad ASJ exome

AF:

0.00799

Gnomad EAS exome

AF:

0.000648

Gnomad FIN exome

AF:

0.00338

Gnomad NFE exome

AF:

0.00708

Gnomad OTH exome

AF:

0.00418

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000168

AC:

203

AN:

1205198

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

104

AN XY:

606966

show subpopulations

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

African (AFR)

AF:

0.0000695

AC:

AN:

28792

American (AMR)

AF:

0.0000726

AC:

AN:

41302

Ashkenazi Jewish (ASJ)

AF:

0.0000851

AC:

AN:

23492

East Asian (EAS)

AF:

0.00

AC:

AN:

37540

South Asian (SAS)

AF:

0.000604

AC:

AN:

79452

European-Finnish (FIN)

AF:

0.000159

AC:

AN:

50286

Middle Eastern (MID)

AF:

0.000395

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.000147

AC:

131

AN:

888282

Other (OTH)

AF:

0.000137

AC:

AN:

50988

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.278

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000632

AC:

AN:

126580

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

61712

show subpopulations

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

African (AFR)

AF:

0.0000300

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

12702

Ashkenazi Jewish (ASJ)

AF:

0.000972

AC:

AN:

3086

East Asian (EAS)

AF:

0.00

AC:

AN:

4508

South Asian (SAS)

AF:

0.00

AC:

AN:

3686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000695

AC:

AN:

57572

Other (OTH)

AF:

0.00

AC:

AN:

1680

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000510703), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.269

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0539

Hom.:

384

ExAC

AF:

0.0394

AC:

4674

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.018

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

PhyloP100

0.30

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.9

REVEL

Benign

0.088

Sift

Benign

0.065

Sift4G

Uncertain

0.021

Polyphen

0.0010

Vest4

0.13

MPC

0.69

ClinPred

0.024

GERP RS

0.19

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over