rs61752106

chr17-35577093-G-Achr17-35577093-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000286.3(PEX12):c.625C>T(p.Gln209Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000821 in 1,461,880 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PEX12 NM_000286.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35577093-G-A is Pathogenic according to our data. Variant chr17-35577093-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX12	NM_000286.3	c.625C>T	p.Gln209Ter	stop_gained	2/3	ENST00000225873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX12	ENST00000225873.9	c.625C>T	p.Gln209Ter	stop_gained	2/3	1	NM_000286.3	P1
PEX12	ENST00000586663.2	c.625C>T	p.Gln209Ter	stop_gained	2/3	1
PEX12	ENST00000585380.1	c.625C>T	p.Gln209Ter	stop_gained	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251486 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Gln209*) in the PEX12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs61752106, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 14571262). ClinVar contains an entry for this variant (Variation ID: 555548). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

Peroxisome biogenesis disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 13, 2018

Variant summary: PEX12 c.625C>T (p.Gln209X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Leu245fsX19). The variant allele was found at a frequency of 2.8e-05 in 246262 control chromosomes. c.625C>T has been reported in the literature in individuals affected with Zellweger Syndrome. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence showing a reduction in PEX12 mRNA in patient fibroblasts, as well as <10% of normal activity in dihydroxyacetonephosphate acyltransferase (DHAPAT) activity (Gootjes_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A
Vest4		0.79
GERP RS		4.4

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

Other links and lift over

dbSNP: rs61752106; hg19: chr17-33904112; COSMIC: COSV56777570; COSMIC: COSV56777570;