rs38809

Positions:

• chr7-92518270-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000466.3(PEX1):​c.358-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 1,452,726 control chromosomes in the GnomAD database, including 560,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57569 hom., cov: 32)
  • Exomes 𝑓: 0.88 (502642 hom.)
• Consequence: PEX1 NM_000466.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.486

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-92518270-C-T is Benign according to our data. Variant chr7-92518270-C-T is described in ClinVar as [Benign]. Clinvar id is 93112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92518270-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.358-15G>A		intron_variant		ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.358-15G>A		intron_variant			NP_001269606.1
PEX1	NM_001282678.2	c.-267-15G>A		intron_variant			NP_001269607.1
PEX1	XM_047420472.1	c.358-15G>A		intron_variant			XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.358-15G>A		intron_variant		1	NM_000466.3	ENSP00000248633.4
PEX1	ENST00000428214.5	c.358-15G>A		intron_variant		1		ENSP00000394413.1
PEX1	ENST00000438045.5	c.273+3832G>A		intron_variant		2		ENSP00000410438.1
PEX1	ENST00000484913.5	n.397-15G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132252 AN: 152098 Hom.: 57539 Cov.: 32

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.915

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.871

GnomAD3 exomes AF: 0.883 AC: 221609 AN: 251108 Hom.: 97999 AF XY: 0.883 AC XY: 119821 AN XY: 135738

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.924

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.960

Gnomad SAS exome AF: 0.898

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.882

GnomAD4 exome AF: 0.879 AC: 1142857 AN: 1300512 Hom.: 502642 Cov.: 19 AF XY: 0.879 AC XY: 577003 AN XY: 656152

Gnomad4 AFR exome AF: 0.850

Gnomad4 AMR exome AF: 0.921

Gnomad4 ASJ exome AF: 0.892

Gnomad4 EAS exome AF: 0.959

Gnomad4 SAS exome AF: 0.900

Gnomad4 FIN exome AF: 0.827

Gnomad4 NFE exome AF: 0.875

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.869 AC: 132335 AN: 152214 Hom.: 57569 Cov.: 32 AF XY: 0.869 AC XY: 64680 AN XY: 74422

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.916

Gnomad4 ASJ AF: 0.888

Gnomad4 EAS AF: 0.957

Gnomad4 SAS AF: 0.910

Gnomad4 FIN AF: 0.829

Gnomad4 NFE AF: 0.865

Gnomad4 OTH AF: 0.872

Alfa AF: 0.862 Hom.: 10515

Bravo AF: 0.877

Asia WGS AF: 0.902 AC: 3139 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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: 88% of total chromosomes in ExAC -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Zellweger spectrum disorders Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Heimler syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Peroxisome biogenesis disorder 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.93
DANN	Benign	0.56

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: rs38809; hg19: chr7-92147584;