NM_001032382.2:c.461_462dupAG

Variant names:

• chrX-48902390-C-CAG
• rs606231193
• NM_001032382.2:c.461_462dupAG

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.461_462dupAG​(p.Arg155SerfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PQBP1 NM_001032382.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.47
• 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-C-CAG is Pathogenic according to our data. Variant chrX-48902390-C-CAG is described in ClinVar as Pathogenic. ClinVar VariationId is 10979.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.461_462dupAG	p.Arg155SerfsTer41	frameshift	Exon 5 of 7	NP_001027554.1	O60828-1
	PQBP1	NM_001032381.2		c.461_462dupAG	p.Arg155SerfsTer41	frameshift	Exon 5 of 7	NP_001027553.1	A0A0S2Z4V5
	PQBP1	NM_001032383.2		c.461_462dupAG	p.Arg155SerfsTer41	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.461_462dupAG	p.Arg155SerfsTer41	frameshift	Exon 5 of 7	ENSP00000391759.2	O60828-1
	PQBP1	ENST00000218224.9	TSL:1	c.461_462dupAG	p.Arg155SerfsTer41	frameshift	Exon 4 of 6	ENSP00000218224.4	O60828-1
	PQBP1	ENST00000463529.4	TSL:1	n.461_462dupAG		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 110939 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000594 AC: 1 AN: 168290 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095228 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 360906

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 34808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

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: 4132

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840548

Other (OTH) AF: 0.00 AC: 0 AN: 45992

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 110992 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33300

African (AFR) AF: 0.00 AC: 0 AN: 30589

American (AMR) AF: 0.00 AC: 0 AN: 10469

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2629

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52767

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Renpenning syndrome (5)
1	-	-	not provided (1)
1	-	-	PQBP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs606231193; hg19: chrX-48759667;