rs741932

chrX-48901927-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001032382.2(PQBP1):c.180-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (13103 hom., 18635 hem., cov: 22)
  • Exomes 𝑓: 0.61 (134857 hom. 222435 hem.)
  • Failed GnomAD Quality Control
• Consequence: PQBP1 NM_001032382.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.08010
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.58

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-48901927-C-T is Benign according to our data. Variant chrX-48901927-C-T is described in ClinVar as [Benign]. Clinvar id is 95309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48901927-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 13112 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.180-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.180-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 63578 AN: 109812 Hom.: 13112 Cov.: 22 AF XY: 0.579 AC XY: 18602 AN XY: 32138

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.585

GnomAD3 exomes AF: 0.606 AC: 110628 AN: 182555 Hom.: 21111 AF XY: 0.618 AC XY: 41414 AN XY: 67051

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.754

Gnomad SAS exome AF: 0.733

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.602

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.607 AC: 666188 AN: 1097790 Hom.: 134857 Cov.: 62 AF XY: 0.612 AC XY: 222435 AN XY: 363180

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.528

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.756

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.586

Gnomad4 NFE exome AF: 0.600

Gnomad4 OTH exome AF: 0.609

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.579 AC: 63595 AN: 109868 Hom.: 13103 Cov.: 22 AF XY: 0.579 AC XY: 18635 AN XY: 32204

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.734

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.591

Gnomad4 OTH AF: 0.578

Alfa AF: 0.586 Hom.: 22624

Bravo AF: 0.578

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Renpenning syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.080
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.020		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: rs741932; hg19: chrX-48759204;