X-48898423-C-T

Variant names:

• chrX-48898423-C-T
• rs150603792
• ENST00000473764.6:n.339C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001032382.2(PQBP1):​c.-18-69C>T variant causes a intron 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 NM_001032382.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 1 publications found

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]

PQBP1 Gene-Disease associations (from GenCC):

• Renpenning syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• hamel cerebro-palato-cardiac syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Golabi-Ito-hall type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Porteous type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Sutherland-Haan type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.-18-69C>T		intron_variant	Intron 1 of 6	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7	c.-18-69C>T		intron_variant	Intron 1 of 6	1	NM_001032382.2	ENSP00000391759.2

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 242 AN: 111648 Hom.: 0 Cov.: 22

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

African (AFR) AF: 0.000230 AC: 5 AN: 21734

American (AMR) AF: 0.000917 AC: 30 AN: 32701

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 108 AN: 17774

East Asian (EAS) AF: 0.00 AC: 0 AN: 28521

South Asian (SAS) AF: 0.000478 AC: 23 AN: 48097

European-Finnish (FIN) AF: 0.00870 AC: 345 AN: 39658

Middle Eastern (MID) AF: 0.00188 AC: 7 AN: 3716

European-Non Finnish (NFE) AF: 0.00294 AC: 1883 AN: 640113

Other (OTH) AF: 0.00254 AC: 98 AN: 38598

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

African (AFR) AF: 0.000618 AC: 19 AN: 30761

American (AMR) AF: 0.00333 AC: 35 AN: 10498

Ashkenazi Jewish (ASJ) AF: 0.00492 AC: 13 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2701

European-Finnish (FIN) AF: 0.00751 AC: 45 AN: 5989

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00241 AC: 128 AN: 53118

Other (OTH) AF: 0.00131 AC: 2 AN: 1522

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.5
PromoterAI		-0.0032	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150603792; hg19: chrX-48755706;