Genetic Variant ENST00000399084.5:c.-63-116G>A (chr6-32666786-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000399084.5(HLA-DQB1):c.-63-116G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 211,278 control chromosomes in the GnomAD database, including 1,033 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 958 hom., cov: 8)

Exomes 𝑓: 0.023 ( 75 hom. )

Consequence

HLA-DQB1
ENST00000399084.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.13

Publications

8 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 (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5 link	c.-179G>A		upstream_gene_variant		ENST00000434651.7	NP_002114.3	P01920Q5Y7D6Q5Y7A9
HLA-DQB1	NM_001243961.2 link	c.-179G>A		upstream_gene_variant			NP_001230890.1	Q5SU54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7 link	c.-179G>A		upstream_gene_variant		6	NM_002123.5	ENSP00000407332.2		Q5Y7D6
HLA-DQB1	ENST00000374943.8 link	c.-179G>A		upstream_gene_variant		6		ENSP00000364080.4		Q5SU54

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

15164

AN:

70280

Hom.:

958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.0988

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.213

GnomAD4 exome

AF:

0.0234

AC:

3294

AN:

140942

Hom.:

AF XY:

0.0241

AC XY:

1796

AN XY:

74446

show subpopulations

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

African (AFR)

AF:

0.0205

AC:

AN:

3760

American (AMR)

AF:

0.00996

AC:

AN:

3114

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3560

East Asian (EAS)

AF:

0.00159

AC:

AN:

8786

South Asian (SAS)

AF:

0.0364

AC:

425

AN:

11666

European-Finnish (FIN)

AF:

0.0110

AC:

148

AN:

13468

Middle Eastern (MID)

AF:

0.0710

AC:

AN:

704

European-Non Finnish (NFE)

AF:

0.0262

AC:

2295

AN:

87606

Other (OTH)

AF:

0.0260

AC:

215

AN:

8278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.327

Heterozygous variant carriers

206

411

617

822

1028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.216

AC:

15169

AN:

70336

Hom.:

958

Cov.:

AF XY:

0.207

AC XY:

7117

AN XY:

34406

show subpopulations

African (AFR)

AF:

0.217

AC:

4302

AN:

19828

American (AMR)

AF:

0.179

AC:

997

AN:

5568

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

187

AN:

1112

East Asian (EAS)

AF:

0.0983

AC:

226

AN:

2298

South Asian (SAS)

AF:

0.200

AC:

505

AN:

2522

European-Finnish (FIN)

AF:

0.150

AC:

749

AN:

4980

Middle Eastern (MID)

AF:

0.321

AC:

AN:

106

European-Non Finnish (NFE)

AF:

0.243

AC:

7932

AN:

32684

Other (OTH)

AF:

0.207

AC:

185

AN:

892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

499

998

1498

1997

2496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.4

(source)

DANN

Benign

0.73

PhyloP100

-2.1

PromoterAI

-0.23

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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