X-48898568-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001032382.2(PQBP1):c.59T>A(p.Leu20Gln) variant causes a missense change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PQBP1 NM_001032382.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2091443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.59T>A	p.Leu20Gln	missense_variant	2/7	ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.59T>A	p.Leu20Gln	missense_variant	2/7	1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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 04, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PQBP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 20 of the PQBP1 protein (p.Leu20Gln). 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	0.22
BayesDel_addAF	Benign	-0.00062	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;.;.;.;.;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.34	N;N;N;N;N;N;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.77	N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.59	T;T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;T
Polyphen		0.062	B;P;P;B;P;P;.
Vest4		0.56
MutPred		0.45		Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);Loss of catalytic residue at L20 (P = 0.0069);
MVP		0.87
MPC		1.5
ClinPred		0.48	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48755851;