Genetic Variant HLA-DQB1:p.Val99Ile (chr6-32664882-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002123.5(HLA-DQB1):c.295G>A(p.Val99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,188,672 control chromosomes in the GnomAD database, including 10,563 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.032 ( 651 hom., cov: 20)

Exomes 𝑓: 0.039 ( 9912 hom. )

Consequence

HLA-DQB1
NM_002123.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -13.4

Publications

26 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035562098).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.295G>A	p.Val99Ile	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.295G>A	p.Val99Ile	missense_variant	Exon 2 of 6		NP_001230890.1	Q5SU54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7 link	c.295G>A	p.Val99Ile	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.295G>A	p.Val99Ile	missense_variant	Exon 2 of 6	6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.0320

AC:

3768

AN:

117780

Hom.:

652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.00644

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.0680

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.0256

Gnomad MID

AF:

0.0580

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0371

GnomAD2 exomes

AF:

0.0391

AC:

6440

AN:

164704

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.00298

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0545

Gnomad EAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.00289

Gnomad NFE exome

AF:

0.00889

Gnomad OTH exome

AF:

0.0262

GnomAD4 exome

AF:

0.0386

AC:

41369

AN:

1070812

Hom.:

9912

Cov.:

AF XY:

0.0451

AC XY:

24504

AN XY:

543070

show subpopulations

African (AFR)

AF:

0.0111

AC:

275

AN:

24878

American (AMR)

AF:

0.0538

AC:

2101

AN:

39026

Ashkenazi Jewish (ASJ)

AF:

0.0683

AC:

1531

AN:

22408

East Asian (EAS)

AF:

0.233

AC:

8245

AN:

35458

South Asian (SAS)

AF:

0.217

AC:

15987

AN:

73632

European-Finnish (FIN)

AF:

0.0210

AC:

973

AN:

46428

Middle Eastern (MID)

AF:

0.0738

AC:

329

AN:

4456

European-Non Finnish (NFE)

AF:

0.0126

AC:

9835

AN:

778130

Other (OTH)

AF:

0.0451

AC:

2093

AN:

46396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

463

927

1390

1854

2317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

430

860

1290

1720

2150

<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

AF:

0.0320

AC:

3768

AN:

117860

Hom.:

651

Cov.:

AF XY:

0.0362

AC XY:

2077

AN XY:

57306

show subpopulations

African (AFR)

AF:

0.0150

AC:

459

AN:

30702

American (AMR)

AF:

0.0392

AC:

450

AN:

11484

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

197

AN:

2896

East Asian (EAS)

AF:

0.190

AC:

792

AN:

4164

South Asian (SAS)

AF:

0.214

AC:

753

AN:

3518

European-Finnish (FIN)

AF:

0.0256

AC:

208

AN:

8134

Middle Eastern (MID)

AF:

0.0619

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0152

AC:

829

AN:

54394

Other (OTH)

AF:

0.0392

AC:

AN:

1582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0180

Hom.:

ExAC

AF:

0.0656

AC:

7587

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0010

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.00067

T;T;.;.

Eigen

Benign

-2.9

Eigen_PC

Benign

-3.0

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.32

T;T;.;T

MetaRNN

Benign

0.036

T;T;T;T

MetaSVM

Benign

-0.89

PhyloP100

-13

PrimateAI

Benign

0.29

PROVEAN

Benign

0.50

N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.025

MPC

0.44

ClinPred

0.015

GERP RS

-7.6

gMVP

0.056

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over