Variant X-48902390-CAGAG-CAGAGAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001032382.2(PQBP1):c.461_462dupAG(p.Arg155SerfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,228 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: 22)

Exomes 𝑓: 0.0000018 ( 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:6

Conservation

PhyloP100: 1.47

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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-C-CAG is Pathogenic according to our data. Variant chrX-48902390-C-CAG is described in ClinVar as [Pathogenic]. Clinvar id is 10979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PQBP1	NM_001032382.2 link	c.461_462dupAG	p.Arg155SerfsTer41	frameshift_variant	Exon 5 of 7	ENST00000447146.7	NP_001027554.1	O60828-1A0A0S2Z4V5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7 link	c.461_462dupAG	p.Arg155SerfsTer41	frameshift_variant	Exon 5 of 7	1	NM_001032382.2	ENSP00000391759.2		O60828-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110939

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33237

FAILED QC

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

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1095228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

110992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33300

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renpenning syndrome

Pathogenic:4

Molecular Genetics Lab, CHRU Brest

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:1

Aug 01, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461_462dupAG variant, denoted as 3898_3899dupAG due to alternative nomenclature, in the PQBP1 gene has been reported previously to segregate in affected males from two families with X-linked mental retardation, including one family with Sutherland-Haan syndrome (Kalscheuer et al., 2003). Functional studies of the variant, denoted as 3898_3899dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein is not properly localized in the nucleus (Kalscheuer et al., 2003). In addition, functional studies of the variant, denoted as c.463_464dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein affects fragile X mental retardation protein (FMRP) degradation leading to FMRP-dependent synaptic defects (Zhang et al., 2017). The c.461_462dupAG variant causes a frameshift starting with codon Arginine 155, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Arg155SerfsX41. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.461_462dupAG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.461_462dupAG as a pathogenic variant. -

PQBP1-related disorder

Pathogenic:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PQBP1 c.461_462dupAG variant is predicted to result in a frameshift and premature protein termination (p.Arg155Serfs*41). This variant has been reported to segregate with disease in two families with X-linked intellectual disability (families with AG duplication in Kalscheuer et al. 2003. PubMed ID: 14634649). In vitro experimental studies indicate this variant impacts protein function (reported as c.463_464dupAG in Mizuguchi et al. 2014. PubMed ID: 24781215 and Zhang et al. 2017. PubMed ID: 28073926). This variant is reported in 0.0014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PQBP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over