NM_001032382.2:c.397C>G

Variant names:

• chrX-48902337-C-G
• rs201489630
• NM_001032382.2:c.397C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001032382.2(PQBP1):​c.397C>G​(p.Arg133Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,097,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R133W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000021 (0 hom. 7 hem.)
• Consequence: PQBP1 NM_001032382.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23090246).
• BS2: High Hemizygotes in GnomAdExome4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	NM_001032382.2	MANE Select	c.397C>G	p.Arg133Gly	missense	Exon 5 of 7	NP_001027554.1
	PQBP1	NM_001032381.2		c.397C>G	p.Arg133Gly	missense	Exon 5 of 7	NP_001027553.1
	PQBP1	NM_001032383.2		c.397C>G	p.Arg133Gly	missense	Exon 5 of 7	NP_001027555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.397C>G	p.Arg133Gly	missense	Exon 5 of 7	ENSP00000391759.2
	PQBP1	ENST00000218224.9	TSL:1	c.397C>G	p.Arg133Gly	missense	Exon 4 of 6	ENSP00000218224.4
	PQBP1	ENST00000463529.4	TSL:1	n.397C>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180762 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 23 AN: 1097431 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 7 AN XY: 362963

African (AFR) AF: 0.00 AC: 0 AN: 26336

American (AMR) AF: 0.00 AC: 0 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 53959

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000261 AC: 22 AN: 841776

Other (OTH) AF: 0.0000217 AC: 1 AN: 46074

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.39
Sift	Benign	0.092	T
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.69
MutPred		0.39		Loss of MoRF binding (P = 0.0033)
MVP		0.90
MPC		0.97
ClinPred		0.26	T
GERP RS		4.7
Varity_R		0.23
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201489630; hg19: chrX-48759614;