ENST00000218224.9:c.-303G>T

Variant names:

• chrX-48898207-G-T
• rs41312118
• ENST00000218224.9:c.-303G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000218224.9(PQBP1):​c.-303G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 986,599 control chromosomes in the GnomAD database, including 92 homozygotes. There are 3,804 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., 285 hem., cov: 23)
  • Exomes 𝑓: 0.015 (81 hom. 3519 hem.)
• Consequence: PQBP1 ENST00000218224.9 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.723
• Publications: 1 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=-0.79).
• BP6: Variant X-48898207-G-T is Benign according to our data. Variant chrX-48898207-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 677296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00998 (1122/112454) while in subpopulation NFE AF = 0.0155 (825/53259). AF 95% confidence interval is 0.0146. There are 11 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.-19+125G>T		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+125G>T		intron_variant	Intron 1 of 6	1	NM_001032382.2	ENSP00000391759.2

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1123 AN: 112401 Hom.: 11 Cov.: 23

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0589

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.0313

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.00858

GnomAD4 exome AF: 0.0147 AC: 12891 AN: 874145 Hom.: 81 Cov.: 14 AF XY: 0.0158 AC XY: 3519 AN XY: 222609

African (AFR) AF: 0.00147 AC: 31 AN: 21128

American (AMR) AF: 0.00441 AC: 106 AN: 24019

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 439 AN: 14975

East Asian (EAS) AF: 0.00 AC: 0 AN: 21216

South Asian (SAS) AF: 0.000548 AC: 24 AN: 43762

European-Finnish (FIN) AF: 0.00455 AC: 133 AN: 29248

Middle Eastern (MID) AF: 0.00163 AC: 4 AN: 2450

European-Non Finnish (NFE) AF: 0.0173 AC: 11744 AN: 680774

Other (OTH) AF: 0.0112 AC: 410 AN: 36573

GnomAD4 genome AF: 0.00998 AC: 1122 AN: 112454 Hom.: 11 Cov.: 23 AF XY: 0.00823 AC XY: 285 AN XY: 34612

African (AFR) AF: 0.00187 AC: 58 AN: 30972

American (AMR) AF: 0.00751 AC: 80 AN: 10654

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 83 AN: 2653

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2756

European-Finnish (FIN) AF: 0.00357 AC: 22 AN: 6164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0155 AC: 825 AN: 53259

Other (OTH) AF: 0.00847 AC: 13 AN: 1534

Alfa AF: 0.0112 Hom.: 64

Bravo AF: 0.00975

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.48
PhyloP100		0.72
PromoterAI		-0.0038	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs41312118; hg19: chrX-48755490; COSMIC: COSV54429328; COSMIC: COSV54429328;