rs1557041239

chrX-48901982-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001032382.2(PQBP1):c.232C>T(p.Pro78Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P78Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PQBP1 NM_001032382.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.32

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain WW (size 34) in uniprot entity PQBP1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001032382.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48901983-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1802539.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant X-48901982-C-T is Pathogenic according to our data. Variant chrX-48901982-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521007.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PQBP1	NM_001032382.2	c.232C>T	p.Pro78Ser	missense_variant	4/7	ENST00000447146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PQBP1	ENST00000447146.7	c.232C>T	p.Pro78Ser	missense_variant	4/7	1	NM_001032382.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;.;.;.;.;.
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D;D;D;T
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.69
MutPred		0.63		Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);Loss of catalytic residue at P78 (P = 0.0064);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557041239; hg19: chrX-48759259;