X-48898097-G-A

Variant names:

• chrX-48898097-G-A
• rs112261029
• ENST00000218224.9: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
• 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]

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 VariationId is 1236832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032383.2. 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.-19+15G>A		intron	N/A	NP_001027554.1	O60828-1
	TIMM17B	NM_001167947.2		c.-103C>T		5_prime_UTR	Exon 1 of 8	NP_001161419.1	O60830-2
	TIMM17B	NM_005834.5		c.-103C>T		5_prime_UTR	Exon 1 of 7	NP_005825.1	O60830-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PQBP1	ENST00000218224.9	TSL:1	c.-413G>A		5_prime_UTR	Exon 1 of 6	ENSP00000218224.4	O60828-1
	TIMM17B	ENST00000376582.7	TSL:1	c.-103C>T		5_prime_UTR	Exon 1 of 7	ENSP00000365766.3	O60830-1
	PQBP1	ENST00000447146.7	TSL:1 MANE Select	c.-19+15G>A		intron	N/A	ENSP00000391759.2	O60828-1

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

African (AFR) AF: 0.00724 AC: 151 AN: 20843

American (AMR) AF: 0.0373 AC: 497 AN: 13318

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 1176 AN: 12006

East Asian (EAS) AF: 0.0000489 AC: 1 AN: 20434

South Asian (SAS) AF: 0.0129 AC: 501 AN: 38941

European-Finnish (FIN) AF: 0.0470 AC: 785 AN: 16713

Middle Eastern (MID) AF: 0.0631 AC: 139 AN: 2204

European-Non Finnish (NFE) AF: 0.0659 AC: 49313 AN: 748614

Other (OTH) 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

African (AFR) AF: 0.00855 AC: 261 AN: 30538

American (AMR) AF: 0.0408 AC: 426 AN: 10441

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 240 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3495

South Asian (SAS) AF: 0.0132 AC: 34 AN: 2583

European-Finnish (FIN) AF: 0.0488 AC: 289 AN: 5926

Middle Eastern (MID) AF: 0.0417 AC: 9 AN: 216

European-Non Finnish (NFE) AF: 0.0647 AC: 3417 AN: 52782

Other (OTH) AF: 0.0593 AC: 89 AN: 1502

Alfa AF: 0.0556 Hom.: 447

Bravo AF: 0.0430

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.70
PhyloP100		0.20
PromoterAI		-0.030	Neutral
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

Other links and lift over

dbSNP: rs112261029; hg19: chrX-48755380;