dbSNP rs9274407: HLA-DQB1:p.Phe41Cys (chr6-32665055-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002123.5(HLA-DQB1):c.122T>G(p.Phe41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0000077 ( 0 hom., cov: 20)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11160529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.122T>G	p.Phe41Cys	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.122T>G	p.Phe41Cys	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.122T>G	p.Phe41Cys	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.122T>G	p.Phe41Cys	missense_variant	Exon 2 of 6	6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.00000768

AC:

AN:

130260

Hom.:

Cov.:

show subpopulations

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:

0.0000168

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

176342

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

8.18e-7

AC:

AN:

1222162

Hom.:

Cov.:

AF XY:

0.00000163

AC XY:

AN XY:

612118

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27068

American (AMR)

AF:

0.00

AC:

AN:

39622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23026

East Asian (EAS)

AF:

0.00

AC:

AN:

36414

South Asian (SAS)

AF:

0.00

AC:

AN:

74884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

916244

Other (OTH)

AF:

0.00

AC:

AN:

50720

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000768

AC:

AN:

130260

Hom.:

Cov.:

AF XY:

0.0000158

AC XY:

AN XY:

63264

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

34006

American (AMR)

AF:

0.00

AC:

AN:

13492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3180

East Asian (EAS)

AF:

0.00

AC:

AN:

4644

South Asian (SAS)

AF:

0.00

AC:

AN:

3692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

59396

Other (OTH)

AF:

0.00

AC:

AN:

1708

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0010

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.35

T;T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.021

T;T;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.59

PhyloP100

-7.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.076

T;T;T;T

Polyphen

0.81

P;.;B;B

Vest4

0.24

MutPred

0.26

Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);

MVP

0.055

MPC

1.2

ClinPred

0.84

GERP RS

-8.3

gMVP

0.56

Mutation Taster

=95/5

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over