rs147530802

Positions:

• chr17-35577920-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000286.3(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (41 hom.)
• Consequence: PEX12 NM_000286.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.26

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 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	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	UniProt
PEX12	ENST00000225873.9	c.102A>T	p.Arg34Ser	missense_variant	1/3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2	n.102A>T		non_coding_transcript_exon_variant	1/3	1		ENSP00000466894.2
PEX12	ENST00000585380.1	c.102A>T	p.Arg34Ser	missense_variant	2/3	4		ENSP00000466280.1

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 757 AN: 152110 Hom.: 5 Cov.: 32

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.: 14 AF XY: 0.00611 AC XY: 830 AN XY: 135908

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.: 41 Cov.: 31 AF XY: 0.00525 AC XY: 3815 AN XY: 727240

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.: 5 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74434

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.: 3

Bravo AF: 0.00365

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	-	- -
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	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. -
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 -

not provided Benign:4

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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
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	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.92	.;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs147530802; hg19: chr17-33904939;