Genetic Variant HLA-DQB1:p.Phe41Tyr (chr6-32665055-A-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.122T>A(p.Phe41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,307,038 control chromosomes in the GnomAD database, including 424,334 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 0.76 ( 39960 hom., cov: 20)

Exomes 𝑓: 0.76 ( 384374 hom. )

Consequence

HLA-DQB1
NM_002123.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -7.44

Publications

72 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=7.067431E-7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.122T>A	p.Phe41Tyr	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3
HLA-DQB1	NM_001243961.2 link	c.122T>A	p.Phe41Tyr	missense_variant	Exon 2 of 6		NP_001230890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7 link	c.122T>A	p.Phe41Tyr	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8 link	c.122T>A	p.Phe41Tyr	missense_variant	Exon 2 of 6	6		ENSP00000364080.4

Frequencies

GnomAD3 genomes

AF:

0.757

AC:

97383

AN:

128718

Hom.:

39939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.673

Gnomad AMI

AF:

0.844

Gnomad AMR

AF:

0.789

Gnomad ASJ

AF:

0.910

Gnomad EAS

AF:

0.723

Gnomad SAS

AF:

0.757

Gnomad FIN

AF:

0.734

Gnomad MID

AF:

0.860

Gnomad NFE

AF:

0.791

Gnomad OTH

AF:

0.814

GnomAD2 exomes

AF:

0.774

AC:

136420

AN:

176342

AF XY:

0.785

show subpopulations

Gnomad AFR exome

AF:

0.606

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.914

Gnomad EAS exome

AF:

0.730

Gnomad FIN exome

AF:

0.713

Gnomad NFE exome

AF:

0.795

Gnomad OTH exome

AF:

0.775

GnomAD4 exome

AF:

0.757

AC:

892271

AN:

1178198

Hom.:

384374

Cov.:

AF XY:

0.760

AC XY:

449379

AN XY:

591258

show subpopulations

African (AFR)

AF:

0.621

AC:

15614

AN:

25152

American (AMR)

AF:

0.763

AC:

29620

AN:

38838

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

20408

AN:

22790

East Asian (EAS)

AF:

0.636

AC:

22647

AN:

35604

South Asian (SAS)

AF:

0.760

AC:

56176

AN:

73872

European-Finnish (FIN)

AF:

0.734

AC:

35469

AN:

48308

Middle Eastern (MID)

AF:

0.840

AC:

3746

AN:

4458

European-Non Finnish (NFE)

AF:

0.763

AC:

671210

AN:

880120

Other (OTH)

AF:

0.762

AC:

37381

AN:

49056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

4019

8038

12058

16077

20096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14020

28040

42060

56080

70100

<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:

0.756

AC:

97457

AN:

128840

Hom.:

39960

Cov.:

AF XY:

0.752

AC XY:

47115

AN XY:

62656

show subpopulations

African (AFR)

AF:

0.673

AC:

22604

AN:

33574

American (AMR)

AF:

0.788

AC:

10569

AN:

13410

Ashkenazi Jewish (ASJ)

AF:

0.910

AC:

2876

AN:

3160

East Asian (EAS)

AF:

0.722

AC:

3309

AN:

4584

South Asian (SAS)

AF:

0.756

AC:

2753

AN:

3642

European-Finnish (FIN)

AF:

0.734

AC:

6587

AN:

8970

Middle Eastern (MID)

AF:

0.851

AC:

206

AN:

242

European-Non Finnish (NFE)

AF:

0.791

AC:

46463

AN:

58716

Other (OTH)

AF:

0.812

AC:

1391

AN:

1714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

620

1240

1859

2479

3099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.644

Hom.:

1454

ESP6500AA

AF:

0.719

AC:

3001

ESP6500EA

AF:

0.813

AC:

6802

ExAC

AF:

0.779

AC:

93224

Asia WGS

AF:

0.792

AC:

2757

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0010

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0080

T;T;.;.

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.0091

T;T;.;T

MetaRNN

Benign

7.1e-7

T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

-7.4

PrimateAI

Benign

0.30

PROVEAN

Benign

0.95

N;N;N;N

REVEL

Benign

0.065

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.030

ClinPred

0.0087

GERP RS

-8.3

gMVP

0.31

Mutation Taster

=98/2

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