rs147530802

Positions:

chr17-35577920-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000225873.9(PEX12):c.102A>T(p.Arg34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,614,094 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 41 hom. )

Consequence

PEX12
ENST00000225873.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.26

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012576401).

BP6

Variant 17-35577920-T-A is Benign according to our data. Variant chr17-35577920-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 92773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35577920-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00497 (757/152226) while in subpopulation NFE AF= 0.0062 (422/68012). AF 95% confidence interval is 0.00572. There are 5 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX12	NM_000286.3 linkuse as main transcript	c.102A>T	p.Arg34Ser	missense_variant	1/3	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.102A>T	p.Arg34Ser	missense_variant	1/3	1	NM_000286.3	ENSP00000225873	P1
PEX12	ENST00000586663.2 linkuse as main transcript	c.102A>T	p.Arg34Ser	missense_variant	1/3	1		ENSP00000466894
PEX12	ENST00000585380.1 linkuse as main transcript	c.102A>T	p.Arg34Ser	missense_variant	2/3	4		ENSP00000466280

Frequencies

GnomAD3 genomes

AF:

0.00498

AC:

757

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00620

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00573

AC:

1442

AN:

251440

Hom.:

AF XY:

0.00611

AC XY:

830

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00483

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00629

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.00511

AC:

7464

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

3815

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00362

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00512

Gnomad4 FIN exome

AF:

0.0121

Gnomad4 NFE exome

AF:

0.00496

Gnomad4 OTH exome

AF:

0.00498

GnomAD4 genome

AF:

0.00497

AC:

757

AN:

152226

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

397

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00393

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0142

Gnomad4 NFE

AF:

0.00620

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00602

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00574

AC:

697

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Benign by Emory 2014. Has been reported in 2 homozygous individuals of iranian origin, who presented with peroxisomal biogenesis disorder with mild clinical phenotype. Consanguinity in at least one of the families. (Zeharia 2007). Given the high frequency in ExAC, LB -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2022	Variant summary: PEX12 c.102A>T (p.Arg34Ser) results in a non-conservative amino acid change located in the Pex, N-terminal domain (IPR006845) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0058 in 282832 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX12 causing Zellweger Syndrome (0.0016), strongly suggesting that the variant is benign. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and four as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	This variant is associated with the following publications: (PMID: 26643206, 17534573, 15542397) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PEX12: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Peroxisome biogenesis disorder 3A (Zellweger)

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Peroxisome biogenesis disorder type 3B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

PEX12-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T

Eigen

Benign

0.19

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

.;D;D

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.012

D;.;.

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.92

P;P;.

Vest4

0.45

MutPred

0.93

Loss of methylation at R34 (P = 0.0939);Loss of methylation at R34 (P = 0.0939);Loss of methylation at R34 (P = 0.0939);

MVP

0.77

MPC

0.46

ClinPred

0.027

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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