17-35576182-CTG-C

Position:

chr17-35576182-CTG-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_000286.3(PEX12):c.681-3_681-2delCA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.00203 in 1,613,808 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 24 hom. )

Consequence

PEX12
NM_000286.3 splice_acceptor, splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.49

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 -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

BP6

Variant 17-35576182-CTG-C is Benign according to our data. Variant chr17-35576182-CTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 92775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1531/152254) while in subpopulation AFR AF= 0.0348 (1444/41536). AF 95% confidence interval is 0.0333. There are 18 homozygotes in gnomad4. There are 768 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX12	NM_000286.3 linkuse as main transcript	c.681-3_681-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000225873.9	NP_000277.1	O00623

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX12	ENST00000225873.9 linkuse as main transcript	c.681-3_681-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_000286.3	ENSP00000225873.3		O00623
PEX12	ENST00000586663.2 linkuse as main transcript	n.681-3_681-2delCA		splice_acceptor_variant, splice_region_variant, intron_variant		1		ENSP00000466894.2		A0A075B773

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1525

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00267

AC:

663

AN:

248770

Hom.:

AF XY:

0.00193

AC XY:

260

AN XY:

134684

show subpopulations

Gnomad AFR exome

AF:

0.0361

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000629

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00119

AC:

1737

AN:

1461554

Hom.:

AF XY:

0.00106

AC XY:

770

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0400

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.0101

AC:

1531

AN:

152254

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

768

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0348

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00571

Hom.:

Bravo

AF:

0.0115

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2021	Variant summary: PEX12 c.681-3_681-2delCA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0027 in 248770 control chromosomes, predominantly at a frequency of 0.036 within the African or African-American subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 22.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX12 causing Zellweger Syndrome phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Peroxisome biogenesis disorder 3A (Zellweger)

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.47

Position offset: -7

DS_AL_spliceai

0.20

Position offset: -1

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