rs751058068

Positions:

chr17-35577347-GGAA-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_000286.3(PEX12):c.368_370del(p.Leu123del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PEX12
NM_000286.3 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 9.12

Variant links:

Genes affected

PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

PEX12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000286.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-35577347-GGAA-G is Pathogenic according to our data. Variant chr17-35577347-GGAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377276.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX12	NM_000286.3 linkuse as main transcript	c.368_370del	p.Leu123del	inframe_deletion	2/3	ENST00000225873.9	NP_000277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PEX12	ENST00000225873.9 linkuse as main transcript	c.368_370del	p.Leu123del	inframe_deletion	2/3	1	NM_000286.3	ENSP00000225873	P1
PEX12	ENST00000586663.2 linkuse as main transcript	c.368_370del	p.Leu123del	inframe_deletion	2/3	1		ENSP00000466894
PEX12	ENST00000585380.1 linkuse as main transcript	c.368_370del	p.Leu123del	inframe_deletion	3/3	4		ENSP00000466280

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251230

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461848

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -

Peroxisome biogenesis disorder type 3B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 25, 2022

Variant summary: PEX12 c.368_370delTTC (p.Leu123del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251230 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, described as p.Leu123del, has been reported in the literature in the heterozygous state (i.e. without an identified second variant) in at-least one individual, who was affected with mild clinical phenotype of the Zellweger Syndrome spectrum (Soliman_2018). Authors of this study also performed functional studies with patient derived fibroblasts and demonstrated both peroxisomal- and Zellweger-like cytoplasmic catalase localization, decreased cellular peroxisome number, and additional cellular alterations (Soliman_2018). This report does not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Peroxisome biogenesis disorder 3A (Zellweger)

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2022

This variant, c.368_370del, results in the deletion of 1 amino acid(s) of the PEX12 protein (p.Leu123del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751058068, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PEX12-related conditions. ClinVar contains an entry for this variant (Variation ID: 377276). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger)

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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