Genetic Variant NM_002123.5:c.296T>A (chr6-32664881-A-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_002123.5(HLA-DQB1):c.296T>A(p.Val99Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,240,768 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0000076 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

HLA-DQB1
NM_002123.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00700

Publications

6 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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31122667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.296T>A	p.Val99Asp	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.296T>A	p.Val99Asp	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.296T>A	p.Val99Asp	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.296T>A	p.Val99Asp	missense_variant	Exon 2 of 6	6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.00000764

AC:

AN:

130852

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:

0.000213

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

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

185258

AF XY:

0.0000390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000590

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1109802

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

562784

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:

26772

American (AMR)

AF:

0.00

AC:

AN:

41044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22960

East Asian (EAS)

AF:

0.000353

AC:

AN:

36860

South Asian (SAS)

AF:

0.00

AC:

AN:

76848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

803852

Other (OTH)

AF:

0.00

AC:

AN:

47936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002500), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

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

AF:

0.00000764

AC:

AN:

130966

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

63832

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:

34400

American (AMR)

AF:

0.00

AC:

AN:

13198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3162

East Asian (EAS)

AF:

0.000213

AC:

AN:

4690

South Asian (SAS)

AF:

0.00

AC:

AN:

3766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59634

Other (OTH)

AF:

0.00

AC:

AN:

1750

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), 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.:

ExAC

AF:

0.0000338

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.014

T;T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.089

T;T;.;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

-0.0070

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;D

Polyphen

0.23

B;.;B;B

Vest4

0.35

MutPred

0.30

Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);

MVP

0.17

MPC

0.97

ClinPred

0.65

GERP RS

1.2

gMVP

0.51

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over