X-48902390-CAGAG-CAG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001032382.2(PQBP1):c.461_462delAG(p.Glu154AlafsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000457 in 1,094,685 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PQBP1
NM_001032382.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.18

Publications

4 publications found

Variant links:

Genes affected

PQBP1 (HGNC:9330): (polyglutamine binding protein 1) This gene encodes a nuclear polyglutamine-binding protein that is involved with transcription activation. The encoded protein contains a WW domain. Mutations in this gene have been found in patients with Renpenning syndrome 1 and other syndromes with X-linked cognitive disability. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.[provided by RefSeq, Nov 2009]

PQBP1 Gene-Disease associations (from GenCC):

Renpenning syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hamel cerebro-palato-cardiac syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Golabi-Ito-hall type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Porteous type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Sutherland-Haan type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

PQBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-48902390-CAG-C is Pathogenic according to our data. Variant chrX-48902390-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032382.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PQBP1	NM_001032382.2	MANE Select	c.461_462delAG	p.Glu154AlafsTer12	frameshift	Exon 5 of 7	NP_001027554.1	O60828-1
PQBP1	NM_001032381.2		c.461_462delAG	p.Glu154AlafsTer12	frameshift	Exon 5 of 7	NP_001027553.1	A0A0S2Z4V5
PQBP1	NM_001032383.2		c.461_462delAG	p.Glu154AlafsTer12	frameshift	Exon 5 of 7	NP_001027555.1	O60828-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.461_462delAG	p.Glu154AlafsTer12	frameshift	Exon 5 of 7	ENSP00000391759.2	O60828-1
PQBP1	ENST00000218224.9	TSL:1	c.461_462delAG	p.Glu154AlafsTer12	frameshift	Exon 4 of 6	ENSP00000218224.4	O60828-1
PQBP1	ENST00000463529.4	TSL:1	n.461_462delAG		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110937

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

GnomAD2 exomes

AF:

0.0000832

AC:

AN:

168290

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000830

Gnomad AMR exome

AF:

0.0000779

Gnomad ASJ exome

AF:

0.000140

Gnomad EAS exome

AF:

0.000231

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000951

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000457

AC:

AN:

1094685

Hom.:

AF XY:

0.00

AC XY:

AN XY:

360453

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:

26372

American (AMR)

AF:

0.0000862

AC:

AN:

34788

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19291

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30116

South Asian (SAS)

AF:

0.00

AC:

AN:

53563

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840139

Other (OTH)

AF:

0.00

AC:

AN:

45971

⚠️ 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: 0.235

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: AC0

AF:

0.00

AC:

AN:

110937

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33235

African (AFR)

AF:

0.00

AC:

AN:

30519

American (AMR)

AF:

0.00

AC:

AN:

10459

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2629

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2623

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5975

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52773

Other (OTH)

AF:

0.00

AC:

AN:

1494

Alfa

AF:

0.0000353

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renpenning syndrome (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over