X-48902337-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001032382.2(PQBP1):c.397C>T(p.Arg133Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,208,476 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R133Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 10 hem. )

Consequence

PQBP1
NM_001032382.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.94

Publications

2 publications found

Variant links:

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

PQBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2674355).

BP6

Variant X-48902337-C-T is Benign according to our data. Variant chrX-48902337-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547755.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PQBP1	NM_001032382.2	MANE Select	c.397C>T	p.Arg133Trp	missense	Exon 5 of 7	NP_001027554.1	O60828-1
PQBP1	NM_001032381.2		c.397C>T	p.Arg133Trp	missense	Exon 5 of 7	NP_001027553.1	A0A0S2Z4V5
PQBP1	NM_001032383.2		c.397C>T	p.Arg133Trp	missense	Exon 5 of 7	NP_001027555.1	O60828-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.397C>T	p.Arg133Trp	missense	Exon 5 of 7	ENSP00000391759.2	O60828-1
PQBP1	ENST00000218224.9	TSL:1	c.397C>T	p.Arg133Trp	missense	Exon 4 of 6	ENSP00000218224.4	O60828-1
PQBP1	ENST00000463529.4	TSL:1	n.397C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111047

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000478

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:

0.0000387

AC:

AN:

180762

AF XY:

0.0000609

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097429

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362963

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26336

American (AMR)

AF:

0.000114

AC:

AN:

35120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30180

South Asian (SAS)

AF:

0.0000927

AC:

AN:

53959

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

841774

Other (OTH)

AF:

0.0000868

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111047

Hom.:

Cov.:

AF XY:

0.0000599

AC XY:

AN XY:

33387

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30459

American (AMR)

AF:

0.000478

AC:

AN:

10469

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52900

Other (OTH)

AF:

0.00

AC:

AN:

1477

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

PQBP1-related disorder (1)

Renpenning syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.2

PhyloP100

2.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.40

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.65

MutPred

0.37

Gain of ubiquitination at K130 (P = 0.0465)

MVP

0.94

MPC

1.8

ClinPred

0.26

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over