X-48898562-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68

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]

ACMG classification

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	UniProt
PQBP1	NM_001032382.2	c.53A>G	p.Lys18Arg	missense_variant	2/7	ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.53A>G	p.Lys18Arg	missense_variant	2/7	1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 182694 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67394

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: 2 AN: 1097487 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362867

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.: 22

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T;.;.;.;.;.
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
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	T
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	D
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

Other links and lift over

dbSNP: rs782388320; hg19: chrX-48755845;