rs782547972

Positions:

• chrX-48902316-AGGGGCCACGACAAGTCAGACC-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_001032382.2(PQBP1):​c.393_413del​(p.Gly134_Arg140del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00011 in 1,209,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.000091 (0 hom. 25 hem.)
• Consequence: PQBP1 NM_001032382.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 5.63

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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001032382.2.
• BP6: Variant X-48902316-AGGGGCCACGACAAGTCAGACC-A is Benign according to our data. Variant chrX-48902316-AGGGGCCACGACAAGTCAGACC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284597.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000297 (33/111238) while in subpopulation AFR AF= 0.000947 (29/30624). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.393_413del	p.Gly134_Arg140del	inframe_deletion	5/7	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7	c.393_413del	p.Gly134_Arg140del	inframe_deletion	5/7	1	NM_001032382.2	ENSP00000391759	P1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 33 AN: 111185 Hom.: 0 Cov.: 22 AF XY: 0.000179 AC XY: 6 AN XY: 33441

Gnomad AFR AF: 0.000949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 37 AN: 182557 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67145

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000722

Gnomad SAS exome AF: 0.0000528

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000911 AC: 100 AN: 1098036 Hom.: 0 AF XY: 0.0000688 AC XY: 25 AN XY: 363406

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.000171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000265

Gnomad4 SAS exome AF: 0.0000925

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000487

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.000297 AC: 33 AN: 111238 Hom.: 0 Cov.: 22 AF XY: 0.000179 AC XY: 6 AN XY: 33504

Gnomad4 AFR AF: 0.000947

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000564

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 1

Bravo AF: 0.000366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2020	This variant is associated with the following publications: (PMID: 16493439) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2021

The c.393_413del21 (p.G134_R140del) alteration is located in exon 5 (coding exon 4) of the PQBP1 gene. This alteration consists of an in-frame deletion of 21 nucleotides between nucleotide positions c.393 and c.413, resulting in the deletion of 7 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PQBP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782547972; hg19: chrX-48759593;