X-48898207-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000218224.9(PQBP1):c.-303G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 986,599 control chromosomes in the GnomAD database, including 92 homozygotes. There are 3,804 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., 285 hem., cov: 23)
  • Exomes 𝑓: 0.015 (81 hom. 3519 hem.)
• Consequence: PQBP1 ENST00000218224.9 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.723

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=-0.79).
• BP6: Variant X-48898207-G-T is Benign according to our data. Variant chrX-48898207-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 677296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00998 (1122/112454) while in subpopulation NFE AF= 0.0155 (825/53259). AF 95% confidence interval is 0.0146. There are 11 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.-19+125G>T		intron_variant		ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.-19+125G>T		intron_variant		1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1123 AN: 112401 Hom.: 11 Cov.: 23 AF XY: 0.00825 AC XY: 285 AN XY: 34549

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0589

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.0313

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.00858

GnomAD4 exome AF: 0.0147 AC: 12891 AN: 874145 Hom.: 81 Cov.: 14 AF XY: 0.0158 AC XY: 3519 AN XY: 222609

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000548

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00998 AC: 1122 AN: 112454 Hom.: 11 Cov.: 23 AF XY: 0.00823 AC XY: 285 AN XY: 34612

Gnomad4 AFR AF: 0.00187

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.0313

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00357

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.00847

Alfa AF: 0.0112 Hom.: 64

Bravo AF: 0.00975

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.4
Dann	Benign	0.48

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: rs41312118; hg19: chrX-48755490; COSMIC: COSV54429328; COSMIC: COSV54429328;