Variant X-48898562-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001032382.2(PQBP1):c.53A>G(p.Lys18Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

PQBP1
NM_001032382.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.68

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39798185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PQBP1	NM_001032382.2 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	2/7	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	2/7	1	NM_001032382.2	ENSP00000391759	P1	O60828-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182694

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000182

AC:

AN:

1097487

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362867

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 18 of the PQBP1 protein (p.Lys18Arg). This variant is present in population databases (rs782388320, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PQBP1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;T;.;T;T;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

T;T;.;.;.;.;.

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.40

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.7

L;L;L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.20

T;T;T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T;T

Polyphen

0.0040

B;P;P;B;P;P;.

Vest4

0.56

MutPred

0.41

Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);Loss of ubiquitination at K18 (P = 0.0059);

MVP

0.77

MPC

1.6

ClinPred

0.54

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over