X-48898097-G-A

Variant names:

• chrX-48898097-G-A
• rs112261029
• ENST00000218224:c.-413G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.-19+15G>A		intron_variant	Intron 1 of 6	ENST00000447146.7	NP_001027554.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 4780 AN: 110734 Hom.: 110 Cov.: 23

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.: 29 AF XY: 0.0589 AC XY: 16253 AN XY: 275964

Gnomad4 AFR exome AF: 0.00724 AC: 151 AN: 20843

Gnomad4 AMR exome AF: 0.0373 AC: 497 AN: 13318

Gnomad4 ASJ exome AF: 0.0980 AC: 1176 AN: 12006

Gnomad4 EAS exome AF: 0.0000489 AC: 1 AN: 20434

Gnomad4 SAS exome AF: 0.0129 AC: 501 AN: 38941

Gnomad4 FIN exome AF: 0.0470 AC: 785 AN: 16713

Gnomad4 NFE exome AF: 0.0659 AC: 49313 AN: 748614

Gnomad4 Remaining exome AF: 0.0540 AC: 2013 AN: 37299

GnomAD4 genome AF: 0.0431 AC: 4779 AN: 110788 Hom.: 110 Cov.: 23 AF XY: 0.0397 AC XY: 1309 AN XY: 33004

Gnomad4 AFR AF: 0.00855 AC: 0.00854673 AN: 0.00854673

Gnomad4 AMR AF: 0.0408 AC: 0.0408007 AN: 0.0408007

Gnomad4 ASJ AF: 0.0916 AC: 0.0915681 AN: 0.0915681

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0132 AC: 0.013163 AN: 0.013163

Gnomad4 FIN AF: 0.0488 AC: 0.0487681 AN: 0.0487681

Gnomad4 NFE AF: 0.0647 AC: 0.064738 AN: 0.064738

Gnomad4 OTH AF: 0.0593 AC: 0.0592543 AN: 0.0592543

Alfa AF: 0.0556 Hom.: 447

Bravo AF: 0.0430

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112261029; hg19: chrX-48755380;