rs121917899

Positions:

• chrX-48901944-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001032382.2(PQBP1):​c.194A>G​(p.Tyr65Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PQBP1 NM_001032382.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.04

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a mutagenesis_site No effect on transcriptional activation; when associated with A-64 and A-66. Markedly reduced transcriptional activation; when associated with A-52; A-64 and A-66. Abolishes transcriptional activation; when associated with A-52; A-64; A-66 and A-75. (size 0) in uniprot entity PQBP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-48901944-A-G is Pathogenic according to our data. Variant chrX-48901944-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.194A>G	p.Tyr65Cys	missense_variant	4/7	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7	c.194A>G	p.Tyr65Cys	missense_variant	4/7	1	NM_001032382.2	ENSP00000391759.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Renpenning syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 18, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;D;.;D;D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;.;.;.;.
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.95
MutPred		0.88		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92

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

LitVar

Other links and lift over

dbSNP: rs121917899; hg19: chrX-48759221;