X-48898423-C-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.-87C>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 0.00279 in 982,613 control chromosomes in the GnomAD database, including 5 homozygotes. There are 747 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., 71 hem., cov: 22)
  • Exomes 𝑓: 0.0029 (5 hom. 676 hem.)
• Consequence: PQBP1 ENST00000218224.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49

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=-0.78).
• BP6: Variant X-48898423-C-T is Benign according to our data. Variant chrX-48898423-C-T is described in ClinVar as [Benign]. Clinvar id is 368452.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00218 (243/111701) while in subpopulation AMR AF= 0.00333 (35/10498). AF 95% confidence interval is 0.00246. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.-18-69C>T		intron_variant		ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.-18-69C>T		intron_variant		1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 242 AN: 111648 Hom.: 0 Cov.: 22 AF XY: 0.00210 AC XY: 71 AN XY: 33830

Gnomad AFR AF: 0.000619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00492

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00751

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00239

Gnomad OTH AF: 0.00133

GnomAD4 exome AF: 0.00287 AC: 2499 AN: 870912 Hom.: 5 Cov.: 15 AF XY: 0.00277 AC XY: 676 AN XY: 243750

Gnomad4 AFR exome AF: 0.000230

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000478

Gnomad4 FIN exome AF: 0.00870

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00218 AC: 243 AN: 111701 Hom.: 0 Cov.: 22 AF XY: 0.00209 AC XY: 71 AN XY: 33893

Gnomad4 AFR AF: 0.000618

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00492

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00751

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00266 Hom.: 15

Bravo AF: 0.00209

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renpenning syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.18
Dann	Benign	0.89

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: rs150603792; hg19: chrX-48755706;