rs782792216

Variant names:

• chrX-48902481-C-T
• rs782792216
• NM_001032382.2:c.541C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-48902481-C-T
• chrX-48902481-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001032382.2(PQBP1):​c.541C>T​(p.Arg181Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,093,392 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: PQBP1 NM_001032382.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0300
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2557583).
• BP6: Variant X-48902481-C-T is Benign according to our data. Variant chrX-48902481-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 561092.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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.541C>T	p.Arg181Trp	missense	Exon 5 of 7	NP_001027554.1	O60828-1
	PQBP1	NM_001032381.2		c.541C>T	p.Arg181Trp	missense	Exon 5 of 7	NP_001027553.1	A0A0S2Z4V5
	PQBP1	NM_001032383.2		c.541C>T	p.Arg181Trp	missense	Exon 5 of 7	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.541C>T	p.Arg181Trp	missense	Exon 5 of 7	ENSP00000391759.2	O60828-1
	PQBP1	ENST00000218224.9	TSL:1	c.541C>T	p.Arg181Trp	missense	Exon 4 of 6	ENSP00000218224.4	O60828-1
	PQBP1	ENST00000463529.4	TSL:1	n.541C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000354 AC: 6 AN: 169372 AF XY: 0.0000349

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 18 AN: 1093392 Hom.: 0 Cov.: 35 AF XY: 0.0000111 AC XY: 4 AN XY: 359686

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.0000580 AC: 2 AN: 34464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19165

East Asian (EAS) AF: 0.00 AC: 0 AN: 30052

South Asian (SAS) AF: 0.000113 AC: 6 AN: 52955

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 40018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000952 AC: 8 AN: 840270

Other (OTH) AF: 0.0000218 AC: 1 AN: 45955

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000496 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Renpenning syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.030
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.22		Loss of helix (P = 0.0123)
MVP		0.83
MPC		1.8
ClinPred		0.46	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs782792216; hg19: chrX-48759758;