rs606231196

Positions:

• chrX-48902788-G-GC
• chrX-48902788-G-GCCCC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001032382.2(PQBP1):​c.640dup​(p.Arg214ProfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PQBP1 NM_001032382.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.81

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48902788-G-GC is Pathogenic according to our data. Variant chrX-48902788-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 10982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.640dup	p.Arg214ProfsTer13	frameshift_variant	6/7	ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.640dup	p.Arg214ProfsTer13	frameshift_variant	6/7	1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1088506 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 356216

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renpenning syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2013	This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 40-year-old male with intellectual disability, autism, dysmorphic features, strabismus -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Pathogenic, criteria provided, single submitter	research	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	The c.640dupC variant in the PQBP1 gene, reported as c.641insC due to use of alternative nomenclature, segregates with Renpenning syndrome in multiple affected male individuals from a single family in published literature (Lenski et al., 2004). The c.640dupC variant causes a frameshift starting with codon Arginine 214, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Arg214ProfsX13. This variant is predicted to cause loss of normal protein function through protein truncation as the last 52 amino acids of the protein are lost and replaced with 12 incorrect amino acids. The c.640dupC variant is not observed in large population cohorts (Lek et al., 2016). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs606231196; hg19: chrX-48760065;