rs771610641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_002618.4(PEX13):c.89T>C(p.Phe30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,550,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

PEX13
NM_002618.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.06

Variant links:

Genes affected

PEX13 (HGNC:8855): (peroxisomal biogenesis factor 13) This gene encodes a peroxisomal membrane protein that binds the type 1 peroxisomal targeting signal receptor via a SH3 domain located in the cytoplasm. Mutations and deficiencies in peroxisomal protein importing and peroxisome assembly lead to peroxisomal biogenesis disorders, an example of which is Zellweger syndrome. [provided by RefSeq, Oct 2008]

PEX13 links:

PUS10 (HGNC:26505): (pseudouridine synthase 10) Pseudouridination, the isomerization of uridine to pseudouridine, is the most common posttranscriptional nucleotide modification found in RNA and is essential for biologic functions such as spliceosome biogenesis. Pseudouridylate synthases, such as PUS10, catalyze pseudouridination of structural RNAs, including transfer, ribosomal, and splicing RNAs. These enzymes also act as RNA chaperones, facilitating the correct folding and assembly of tRNAs (McCleverty et al., 2007 [PubMed 17900615]).[supplied by OMIM, May 2009]

PUS10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06336415).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000565 (86/152332) while in subpopulation NFE AF= 0.000794 (54/68024). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX13	NM_002618.4 link	c.89T>C	p.Phe30Ser	missense_variant	Exon 1 of 4	ENST00000295030.6	NP_002609.1	Q92968
PUS10	NM_144709.4 link	c.-16+160A>G		intron_variant	Intron 1 of 17	ENST00000316752.11	NP_653310.2	Q3MIT2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX13	ENST00000295030.6 link	c.89T>C	p.Phe30Ser	missense_variant	Exon 1 of 4	1	NM_002618.4	ENSP00000295030.4		Q92968
PUS10	ENST00000316752.11 link	c.-16+160A>G		intron_variant	Intron 1 of 17	1	NM_144709.4	ENSP00000326003.6		Q3MIT2

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000510

AC:

AN:

150968

Hom.:

AF XY:

0.000619

AC XY:

AN XY:

80712

show subpopulations

Gnomad AFR exome

AF:

0.000276

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000914

Gnomad NFE exome

AF:

0.000771

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.000865

AC:

1210

AN:

1398086

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

595

AN XY:

689570

show subpopulations

Gnomad4 AFR exome

AF:

0.0000950

Gnomad4 AMR exome

AF:

0.000420

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000604

GnomAD4 genome

AF:

0.000565

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000306

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2017	- -

Peroxisome biogenesis disorder 11A (Zellweger)

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 30 of the PEX13 protein (p.Phe30Ser). This variant is present in population databases (rs771610641, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PEX13-related conditions. ClinVar contains an entry for this variant (Variation ID: 500639). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.89T>C (p.F30S) alteration is located in exon 1 (coding exon 1) of the PEX13 gene. This alteration results from a T to C substitution at nucleotide position 89, causing the phenylalanine (F) at amino acid position 30 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PEX13-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

The PEX13 c.89T>C variant is predicted to result in the amino acid substitution p.Phe30Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.091% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Peroxisome biogenesis disorder 11A (Zellweger);C3554001:Peroxisome biogenesis disorder 11B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

.;T;T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.35

T;T;T;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.5

.;.;L;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.5

D;D;N;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.021

.;.;D;.

Sift4G

Uncertain

0.0070

D;D;T;D

Polyphen

0.079

.;.;B;.

Vest4

0.53

MVP

0.56

MPC

0.22

ClinPred

0.077

GERP RS

2.5

Varity_R

0.23

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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