chr7-92518266-C-G

Variant names:

• chr7-92518266-C-G
• rs113104510
• NM_000466.3:c.358-11G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000466.3(PEX1):​c.358-11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,477,148 control chromosomes in the GnomAD database, including 1,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (155 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1093 hom.)
• Consequence: PEX1 NM_000466.3 intron
• Scores: Splicing: ADA: 0.00001241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.378
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, Ambry Genetics
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-92518266-C-G is Benign according to our data. Variant chr7-92518266-C-G is described in ClinVar as [Benign]. Clinvar id is 256221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.358-11G>C		intron_variant	Intron 3 of 23	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.358-11G>C		intron_variant	Intron 3 of 22		NP_001269606.1
PEX1	NM_001282678.2	c.-267-11G>C		intron_variant	Intron 3 of 23		NP_001269607.1
PEX1	XM_047420472.1	c.358-11G>C		intron_variant	Intron 3 of 22		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.358-11G>C		intron_variant	Intron 3 of 23	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6132 AN: 152008 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0334 AC: 8393 AN: 251138 AF XY: 0.0334

Gnomad AFR exome AF: 0.0531

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00826

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0380 AC: 50393 AN: 1325022 Hom.: 1093 Cov.: 21 AF XY: 0.0379 AC XY: 25258 AN XY: 666876

African (AFR) AF: 0.0528 AC: 1629 AN: 30838

American (AMR) AF: 0.0149 AC: 664 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 405 AN: 25286

East Asian (EAS) AF: 0.00521 AC: 203 AN: 38952

South Asian (SAS) AF: 0.0261 AC: 2181 AN: 83460

European-Finnish (FIN) AF: 0.0424 AC: 2265 AN: 53358

Middle Eastern (MID) AF: 0.0241 AC: 132 AN: 5484

European-Non Finnish (NFE) AF: 0.0415 AC: 41014 AN: 987394

Other (OTH) AF: 0.0341 AC: 1900 AN: 55688

GnomAD4 genome AF: 0.0404 AC: 6153 AN: 152126 Hom.: 155 Cov.: 32 AF XY: 0.0403 AC XY: 2996 AN XY: 74362

African (AFR) AF: 0.0529 AC: 2193 AN: 41494

American (AMR) AF: 0.0230 AC: 352 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.00985 AC: 51 AN: 5180

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4820

European-Finnish (FIN) AF: 0.0424 AC: 448 AN: 10560

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2836 AN: 68004

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0401 Hom.: 32

Bravo AF: 0.0383

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX1 c.358-11G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction the strenghtening of a canonical splice acceptor site site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4339/121280 control chromosomes (85 homozygotes) at a frequency of 0.0357767, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Zellweger spectrum disorders Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs113104510; hg19: chr7-92147580; COSMIC: COSV104373587;