rs606231193

Positions:

• chrX-48902390-CAGAG-C
• chrX-48902390-CAGAG-CAG
• chrX-48902390-CAGAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001032382.2(PQBP1):​c.459_462del​(p.Arg153SerfsTer41) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000913 in 1,095,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PQBP1 NM_001032382.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 4.18

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]

ACMG classification

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-CAGAG-C is Pathogenic according to our data. Variant chrX-48902390-CAGAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48902390-CAGAG-C is described in Lovd as [Pathogenic]. Variant chrX-48902390-CAGAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.459_462del	p.Arg153SerfsTer41	frameshift_variant	5/7	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7	c.459_462del	p.Arg153SerfsTer41	frameshift_variant	5/7	1	NM_001032382.2	ENSP00000391759	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 360984

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renpenning syndrome Pathogenic:12

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Pathogenic, criteria provided, single submitter	research	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jul 08, 2022	ACMG Criteria: PVS1, PS3, PM2, PP1, PP5; Variant was found in hemizygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Hemizygote Frameshift variant c.451_454delAGAG in Exon 4 of the PQBP1 gene that results in the amino acid substitution p.Arg153fs*41 was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variant ID:10980). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010980, PMID:14634649). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jul 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. There is one report of an affected female carrier (PMID: 31840929). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 4 of 6). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals. This variant has been reported as a recurring, common pathogenic variant (PMID: 31840929, 14634649). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Medical Genetics, University of Torino	Oct 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jun 14, 2016	- -
Pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2022	Additional published functional studies demonstrate a damaging effect causing loss of the YxxPxxVL motif that is essential for binding with the spliceosomal protein U5-15kD (Mizuguchi et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant transcripts were markedly reduced compared to controls, indicating nonsense mediated mRNA decay (Kalscheuer et al. 2003); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19847789, 28795356, 30315573, 20886605, 24781215, 14634649, 26046437, 26350204, 28073926, 25533962, 28152038, 29286531, 30500859, 20950397, 30842647, 30951824, 31316545, 31840929, 31840915, 33258288, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg153Serfs*41) in the PQBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PQBP1 are known to be pathogenic (PMID: 20950397). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Renpenning syndrome (PMID: 20950397, 30500859, 31316545). ClinVar contains an entry for this variant (Variation ID: 10980). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

Hyperactivity;C0454644:Delayed speech and language development;C4551563:Microcephaly Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 16, 2016

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PVS1_very strong;PP5_strong;PM2_supporting -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Raymond Lab, University of Cambridge

Feb 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231193; hg19: chrX-48759667;