Genetic Variant HLA-DQB1:p.Val99Leu (chr6-32664882-C-G) – 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.295G>C(p.Val99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0000084 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000033 ( 0 hom. )

Failed GnomAD Quality Control

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13115796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.295G>C	p.Val99Leu	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.295G>C	p.Val99Leu	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>C	p.Val99Leu	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.295G>C	p.Val99Leu	missense_variant	Exon 2 of 6	6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.00000843

AC:

AN:

118594

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:

0.0000183

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000326

AC:

AN:

1074676

Hom.:

Cov.:

AF XY:

0.0000257

AC XY:

AN XY:

545048

show subpopulations

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

African (AFR)

AF:

0.000120

AC:

AN:

25008

American (AMR)

AF:

0.00

AC:

AN:

39464

Ashkenazi Jewish (ASJ)

AF:

0.0000445

AC:

AN:

22448

East Asian (EAS)

AF:

0.00

AC:

AN:

36156

South Asian (SAS)

AF:

0.00

AC:

AN:

73882

European-Finnish (FIN)

AF:

0.000128

AC:

AN:

46902

Middle Eastern (MID)

AF:

0.000224

AC:

AN:

4468

European-Non Finnish (NFE)

AF:

0.0000282

AC:

AN:

779718

Other (OTH)

AF:

0.0000429

AC:

AN:

46630

⚠️ 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: 0.279

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000843

AC:

AN:

118670

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

57718

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:

30968

American (AMR)

AF:

0.00

AC:

AN:

11620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2904

East Asian (EAS)

AF:

0.00

AC:

AN:

4216

South Asian (SAS)

AF:

0.00

AC:

AN:

3532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0000183

AC:

AN:

54602

Other (OTH)

AF:

0.00

AC:

AN:

1590

⚠️ 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.0010

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.00067

T;T;.;.

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.9

FATHMM_MKL

Benign

0.0031

LIST_S2

Benign

0.33

T;T;.;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

-13

PrimateAI

Benign

0.30

PROVEAN

Benign

0.16

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.084

T;T;T;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.065

MVP

0.088

MPC

0.54

ClinPred

0.13

GERP RS

-7.6

gMVP

0.11

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over