rs12386703

Variant names:

• chr7-92528488-G-C
• rs12386703
• NM_000466.3:c.-53C>G

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.-53C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 1,510,668 control chromosomes in the GnomAD database, including 4,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (483 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4500 hom.)
• Consequence: PEX1 NM_000466.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.442

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-92528488-G-C is Benign according to our data. Variant chr7-92528488-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 256216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92528488-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.-53C>G		5_prime_UTR_variant	Exon 1 of 24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.-53C>G		5_prime_UTR_variant	Exon 1 of 23		NP_001269606.1
PEX1	NM_001282678.2	c.-712C>G		5_prime_UTR_variant	Exon 1 of 24		NP_001269607.1
PEX1	XM_047420472.1	c.-53C>G		5_prime_UTR_variant	Exon 1 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.-53C>G		5_prime_UTR_variant	Exon 1 of 24	1	NM_000466.3	ENSP00000248633.4
PEX1	ENST00000428214.5	c.-53C>G		upstream_gene_variant		1		ENSP00000394413.1
PEX1	ENST00000438045.5	c.-53C>G		upstream_gene_variant		2		ENSP00000410438.1
PEX1	ENST00000484913.5	n.-49C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11705 AN: 152136 Hom.: 485 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.0309

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0876

Gnomad OTH AF: 0.0828

GnomAD4 exome AF: 0.0791 AC: 107427 AN: 1358414 Hom.: 4500 Cov.: 32 AF XY: 0.0786 AC XY: 52369 AN XY: 665874

Gnomad4 AFR exome AF: 0.0691

Gnomad4 AMR exome AF: 0.0609

Gnomad4 ASJ exome AF: 0.0855

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.0715

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0811

Gnomad4 OTH exome AF: 0.0775

GnomAD4 genome AF: 0.0769 AC: 11705 AN: 152254 Hom.: 483 Cov.: 32 AF XY: 0.0769 AC XY: 5724 AN XY: 74438

Gnomad4 AFR AF: 0.0676

Gnomad4 AMR AF: 0.0563

Gnomad4 ASJ AF: 0.0894

Gnomad4 EAS AF: 0.0309

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0876

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.0891 Hom.: 87

Bravo AF: 0.0724

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16088892) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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	-0.78
CADD	Benign	2.7
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12386703; hg19: chr7-92157802;