rs771610641

Positions:

• chr2-61017848-T-C
• chr2-61017848-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.06

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]

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]

ACMG classification

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_exome allele frequency = 0.000865 (1210/1398086) while in subpopulation NFE AF= 0.00102 (1100/1078706). AF 95% confidence interval is 0.000969. There are 0 homozygotes in gnomad4_exome. There are 595 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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/exons	MANE	Protein	UniProt
PEX13	NM_002618.4	c.89T>C	p.Phe30Ser	missense_variant	1/4	ENST00000295030.6	NP_002609.1
PUS10	NM_144709.4	c.-16+160A>G		intron_variant		ENST00000316752.11	NP_653310.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX13	ENST00000295030.6	c.89T>C	p.Phe30Ser	missense_variant	1/4	1	NM_002618.4	ENSP00000295030	P1
PUS10	ENST00000316752.11	c.-16+160A>G		intron_variant		1	NM_144709.4	ENSP00000326003	P1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152214 Hom.: 0 Cov.: 32

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: 77 AN: 150968 Hom.: 0 AF XY: 0.000619 AC XY: 50 AN XY: 80712

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.: 0 Cov.: 30 AF XY: 0.000863 AC XY: 595 AN XY: 689570

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: 86 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74496

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.: 0

Bravo AF: 0.000514

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000306 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2017	- -
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 -

Peroxisome biogenesis disorder 11A (Zellweger) Uncertain:2

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. -
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. -

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	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
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	N
LIST_S2	Benign	0.35	T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	.;.;L;.
MutationTaster	Benign	1.0	D;D;D;N;D
PrimateAI	Pathogenic	0.81	D
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	T
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

Other links and lift over

dbSNP: rs771610641; hg19: chr2-61244983;