rs741932

Variant names:

• chrX-48901927-C-T
• rs741932
• NM_001032382.2:c.180-3C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001032382.2(PQBP1):​c.180-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (13103 hom., 18635 hem., cov: 22)
  • Exomes 𝑓: 0.61 (134857 hom. 222435 hem.)
  • Failed GnomAD Quality Control
• Consequence: PQBP1 NM_001032382.2 splice_region, intron
• Scores: Splicing: ADA: 0.08010
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.58
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• Renpenning syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hamel cerebro-palato-cardiac syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Golabi-Ito-hall type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Porteous type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability, Sutherland-Haan type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-48901927-C-T is Benign according to our data. Variant chrX-48901927-C-T is described in ClinVar as Benign. ClinVar VariationId is 95309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032382.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	NM_001032382.2	MANE Select	c.180-3C>T		splice_region intron	N/A	NP_001027554.1	O60828-1
	PQBP1	NM_001032381.2		c.180-3C>T		splice_region intron	N/A	NP_001027553.1	A0A0S2Z4V5
	PQBP1	NM_001032383.2		c.180-3C>T		splice_region intron	N/A	NP_001027555.1	O60828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.180-3C>T		splice_region intron	N/A	ENSP00000391759.2	O60828-1
	PQBP1	ENST00000218224.9	TSL:1	c.180-3C>T		splice_region intron	N/A	ENSP00000218224.4	O60828-1
	PQBP1	ENST00000474671.6	TSL:1	n.986C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.579 AC: 63578 AN: 109812 Hom.: 13112 Cov.: 22

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.585

GnomAD2 exomes AF: 0.606 AC: 110628 AN: 182555 AF XY: 0.618

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.602

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.607 AC: 666188 AN: 1097790 Hom.: 134857 Cov.: 62 AF XY: 0.612 AC XY: 222435 AN XY: 363180

African (AFR) AF: 0.531 AC: 14009 AN: 26395

American (AMR) AF: 0.528 AC: 18578 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 11904 AN: 19376

East Asian (EAS) AF: 0.756 AC: 22819 AN: 30194

South Asian (SAS) AF: 0.728 AC: 39410 AN: 54141

European-Finnish (FIN) AF: 0.586 AC: 23691 AN: 40411

Middle Eastern (MID) AF: 0.572 AC: 2366 AN: 4135

European-Non Finnish (NFE) AF: 0.600 AC: 505360 AN: 841906

Other (OTH) AF: 0.609 AC: 28051 AN: 46075

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.579 AC: 63595 AN: 109868 Hom.: 13103 Cov.: 22 AF XY: 0.579 AC XY: 18635 AN XY: 32204

African (AFR) AF: 0.528 AC: 15931 AN: 30176

American (AMR) AF: 0.566 AC: 5823 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 1580 AN: 2632

East Asian (EAS) AF: 0.734 AC: 2547 AN: 3471

South Asian (SAS) AF: 0.750 AC: 1926 AN: 2568

European-Finnish (FIN) AF: 0.565 AC: 3265 AN: 5783

Middle Eastern (MID) AF: 0.488 AC: 105 AN: 215

European-Non Finnish (NFE) AF: 0.591 AC: 31048 AN: 52572

Other (OTH) AF: 0.578 AC: 859 AN: 1485

Alfa AF: 0.582 Hom.: 32138

Bravo AF: 0.578

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Renpenning syndrome (2)
-	-	1	History of neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.080
dbscSNV1_RF	Benign	0.23
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

Other links and lift over

dbSNP: rs741932; hg19: chrX-48759204; COSMIC: COSV107208803; COSMIC: COSV107208803;