2-61048535-T-C

Variant names:

• chr2-61048535-T-C
• rs61752115
• NM_002618.4:c.977T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002618.4(PEX13):​c.977T>C​(p.Ile326Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I326M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PEX13 NM_002618.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.58
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 11A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 11B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 2-61048535-T-C is Pathogenic according to our data. Variant chr2-61048535-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7704.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX13	NM_002618.4	c.977T>C	p.Ile326Thr	missense_variant	Exon 4 of 4	ENST00000295030.6	NP_002609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX13	ENST00000295030.6	c.977T>C	p.Ile326Thr	missense_variant	Exon 4 of 4	1	NM_002618.4	ENSP00000295030.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251464 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111964

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000633 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jan 25, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect on peroxisome assembly (Shimozawa et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10332040, 16006427) -

Peroxisome biogenesis disorder Pathogenic:1

Sep 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PEX13 c.977T>C (p.Ile326Thr) results in a non-conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251464 control chromosomes. c.977T>C has been reported in the literature in at-least two individuals affected with Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (Hashimoto_2005, Shimozawa_1999,Liu_1999, Ebberink_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a lower melting temperature (Tm, 30 degree vs 58 degree of WT) in vitro (Hashimoto_2005, Shimozawa_1999), suggesting of unstability of the variant protein. The following publications have been ascertained in the context of this evaluation (PMID: 21031596, 16006427, 10441568, 10332040). ClinVar contains an entry for this variant (Variation ID: 7704). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Peroxisome biogenesis disorder 11B Pathogenic:1

Sep 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Peroxisome biogenesis disorder 11A (Zellweger) Uncertain:1

Nov 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 326 of the PEX13 protein (p.Ile326Thr). This variant is present in population databases (rs61752115, gnomAD 0.0009%). This missense change has been observed in individual(s) with neonatal adrenoleukodystrophy (PMID: 10332040). ClinVar contains an entry for this variant (Variation ID: 7704). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PEX13 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PEX13 function (PMID: 10332040, 16006427, 27827795). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.57	P
Vest4		0.83
MutPred		0.92		Gain of disorder (P = 0.0382);
MVP		0.65
MPC		0.12
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.75
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61752115; hg19: chr2-61275670;