rs606231193

Variant names:

• chrX-48902390-CAGAG-C
• rs606231193
• NM_001032382.2:c.459_462delAGAG

Your query was ambiguous. Multiple possible variants found:

• chrX-48902390-CAGAG-C
• chrX-48902390-CAGAG-CAG
• chrX-48902390-CAGAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001032382.2(PQBP1):​c.459_462delAGAG​(p.Arg153SerfsTer41) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000913 in 1,095,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PQBP1 NM_001032382.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 4.18
• Publications: 4 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: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48902390-CAGAG-C is Pathogenic according to our data. Variant chrX-48902390-CAGAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032382.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	NM_001032382.2	MANE Select	c.459_462delAGAG	p.Arg153SerfsTer41	frameshift	Exon 5 of 7	NP_001027554.1	O60828-1
	PQBP1	NM_001032381.2		c.459_462delAGAG	p.Arg153SerfsTer41	frameshift	Exon 5 of 7	NP_001027553.1	A0A0S2Z4V5
	PQBP1	NM_001032383.2		c.459_462delAGAG	p.Arg153SerfsTer41	frameshift	Exon 5 of 7	NP_001027555.1	O60828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.459_462delAGAG	p.Arg153SerfsTer41	frameshift	Exon 5 of 7	ENSP00000391759.2	O60828-1
	PQBP1	ENST00000218224.9	TSL:1	c.459_462delAGAG	p.Arg153SerfsTer41	frameshift	Exon 4 of 6	ENSP00000218224.4	O60828-1
	PQBP1	ENST00000463529.4	TSL:1	n.459_462delAGAG		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 360984

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 34810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19302

East Asian (EAS) AF: 0.00 AC: 0 AN: 30127

South Asian (SAS) AF: 0.00 AC: 0 AN: 53602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840621

Other (OTH) AF: 0.00 AC: 0 AN: 45994

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	Renpenning syndrome (17)
5	-	-	not provided (5)
1	-	-	Hyperactivity;C0454644:Delayed speech and language development;C4551563:Microcephaly (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs606231193; hg19: chrX-48759667; COSMIC: COSV109404492; COSMIC: COSV109404492;