Genetic Variant NM_002123.5:c.260G>C (chr6-32664917-C-G) – 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.260G>C(p.Arg87Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.35 ( 11130 hom., cov: 20)

Exomes 𝑓: 0.28 ( 55025 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6105175E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.260G>C	p.Arg87Pro	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.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 6	6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

43512

AN:

124172

Hom.:

11128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.456

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.457

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.370

GnomAD2 exomes

AF:

0.338

AC:

52770

AN:

156124

AF XY:

0.335

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.548

Gnomad ASJ exome

AF:

0.485

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.307

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.276

AC:

295407

AN:

1069964

Hom.:

55025

Cov.:

AF XY:

0.279

AC XY:

151372

AN XY:

541638

show subpopulations

African (AFR)

AF:

0.171

AC:

4470

AN:

26066

American (AMR)

AF:

0.460

AC:

17673

AN:

38404

Ashkenazi Jewish (ASJ)

AF:

0.427

AC:

9198

AN:

21560

East Asian (EAS)

AF:

0.398

AC:

13985

AN:

35114

South Asian (SAS)

AF:

0.262

AC:

19699

AN:

75162

European-Finnish (FIN)

AF:

0.288

AC:

13899

AN:

48228

Middle Eastern (MID)

AF:

0.356

AC:

1677

AN:

4706

European-Non Finnish (NFE)

AF:

0.260

AC:

201115

AN:

774738

Other (OTH)

AF:

0.298

AC:

13691

AN:

45986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6129

12259

18388

24518

30647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5248

10496

15744

20992

26240

<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:

0.350

AC:

43542

AN:

124264

Hom.:

11130

Cov.:

AF XY:

0.347

AC XY:

21004

AN XY:

60598

show subpopulations

African (AFR)

AF:

0.255

AC:

8357

AN:

32768

American (AMR)

AF:

0.443

AC:

5520

AN:

12472

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1509

AN:

3044

East Asian (EAS)

AF:

0.457

AC:

2011

AN:

4396

South Asian (SAS)

AF:

0.285

AC:

1025

AN:

3592

European-Finnish (FIN)

AF:

0.287

AC:

2512

AN:

8762

Middle Eastern (MID)

AF:

0.450

AC:

100

AN:

222

European-Non Finnish (NFE)

AF:

0.381

AC:

21536

AN:

56580

Other (OTH)

AF:

0.368

AC:

603

AN:

1640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

701

1402

2103

2804

3505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.168

Hom.:

384

ExAC

AF:

0.366

AC:

43391

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.021

T;T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.14

T;T;.;T

MetaRNN

Benign

0.00016

T;T;T;T

MetaSVM

Benign

-0.91

PhyloP100

0.30

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Benign

0.12

Sift

Benign

0.17

T;T;T;T

Sift4G

Uncertain

0.028

D;D;D;D

Polyphen

0.0030

B;.;B;B

Vest4

0.16

MPC

0.82

ClinPred

0.061

GERP RS

0.19

gMVP

0.55

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