Genetic Variant PQBP1:c.-413G>A (chrX-48898097-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001032383.2(PQBP1):c.-19+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,021,160 control chromosomes in the GnomAD database, including 1,362 homozygotes. There are 17,562 hemizygotes in GnomAD. 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 0.043 ( 110 hom., 1309 hem., cov: 23)

Exomes 𝑓: 0.060 ( 1252 hom. 16253 hem. )

Consequence

PQBP1
NM_001032383.2 splice_region, intron

Scores

Splicing: ADA: 0.0001409

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.205

Variant links:

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 links:

TIMM17B (HGNC:17310): (translocase of inner mitochondrial membrane 17B) This gene encodes a multipass transmembrane protein that forms an integral component of the mitochondrial translocase TIM23 complex. This complex facilitates the transport of mitochondrial proteins from the cytosol across the mitochondrial inner membrane and into the mitochondrion. There is a pseudogene for this gene on chromosome 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

TIMM17B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant X-48898097-G-A is Benign according to our data. Variant chrX-48898097-G-A is described in ClinVar as [Benign]. Clinvar id is 1236832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48898097-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PQBP1	NM_001032382.2 link	c.-19+15G>A		intron_variant	Intron 1 of 6	ENST00000447146.7	NP_001027554.1	O60828-1A0A0S2Z4V5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7 link	c.-19+15G>A		intron_variant	Intron 1 of 6	1	NM_001032382.2	ENSP00000391759.2		O60828-1

Frequencies

GnomAD3 genomes

AF:

0.0432

AC:

4780

AN:

110734

Hom.:

110

Cov.:

AF XY:

0.0397

AC XY:

1307

AN XY:

32940

show subpopulations

Gnomad AFR

AF:

0.00857

Gnomad AMI

AF:

0.0205

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.0464

Gnomad NFE

AF:

0.0647

Gnomad OTH

AF:

0.0600

GnomAD4 exome

AF:

0.0599

AC:

54576

AN:

910372

Hom.:

1252

Cov.:

AF XY:

0.0589

AC XY:

16253

AN XY:

275964

show subpopulations

Gnomad4 AFR exome

AF:

0.00724

Gnomad4 AMR exome

AF:

0.0373

Gnomad4 ASJ exome

AF:

0.0980

Gnomad4 EAS exome

AF:

0.0000489

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.0470

Gnomad4 NFE exome

AF:

0.0659

Gnomad4 OTH exome

AF:

0.0540

GnomAD4 genome

AF:

0.0431

AC:

4779

AN:

110788

Hom.:

110

Cov.:

AF XY:

0.0397

AC XY:

1309

AN XY:

33004

show subpopulations

Gnomad4 AFR

AF:

0.00855

Gnomad4 AMR

AF:

0.0408

Gnomad4 ASJ

AF:

0.0916

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0132

Gnomad4 FIN

AF:

0.0488

Gnomad4 NFE

AF:

0.0647

Gnomad4 OTH

AF:

0.0593

Alfa

AF:

0.0556

Hom.:

447

Bravo

AF:

0.0430

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.6

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.034

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over