dbSNP rs1049130: HLA-DQB1:p.Asn182Lys (chr6-32662082-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002123.5(HLA-DQB1):c.546T>A(p.Asn182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQB1
NM_002123.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.995

Publications

30 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

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.546T>A	p.Asn182Lys	missense	Exon 3 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.546T>A	p.Asn182Lys	missense	Exon 3 of 6	NP_001230890.1	Q5SU54

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.546T>A	p.Asn182Lys	missense	Exon 3 of 5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	TSL:6	c.546T>A	p.Asn182Lys	missense	Exon 3 of 6	ENSP00000364080.4	Q5SU54
HLA-DQB1	ENST00000399084.5	TSL:6	c.546T>A	p.Asn182Lys	missense	Exon 4 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

125872

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1321394

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660986

African (AFR)

AF:

0.00

AC:

AN:

31312

American (AMR)

AF:

0.00

AC:

AN:

37324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23856

East Asian (EAS)

AF:

0.00

AC:

AN:

33660

South Asian (SAS)

AF:

0.00

AC:

AN:

82322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1004528

Other (OTH)

AF:

0.00

AC:

AN:

55138

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

125872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60538

African (AFR)

AF:

0.00

AC:

AN:

35346

American (AMR)

AF:

0.00

AC:

AN:

10854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2938

East Asian (EAS)

AF:

0.00

AC:

AN:

3686

South Asian (SAS)

AF:

0.00

AC:

AN:

4064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58452

Other (OTH)

AF:

0.00

AC:

AN:

1714

Alfa

AF:

0.00

Hom.:

7311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.7

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.025

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.70

M_CAP

Benign

0.0041

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-1.2

PhyloP100

-0.99

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.68

MutPred

0.91

Gain of methylation at N182 (P = 0.0041)

MVP

0.030

MPC

1.6

ClinPred

1.0

GERP RS

-6.3

gMVP

0.55

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over