7-92501975-G-T

Variant names:

• chr7-92501975-G-T
• rs10278857
• NM_000466.3:c.2331C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000466.3(PEX1):​c.2331C>A​(p.Gly777Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 1,613,548 control chromosomes in the GnomAD database, including 681,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.93 (65997 hom., cov: 32)
  • Exomes 𝑓: 0.92 (615917 hom.)
• Consequence: PEX1 NM_000466.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.52
• Publications: 28 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-92501975-G-T is Benign according to our data. Variant chr7-92501975-G-T is described in ClinVar as Benign. ClinVar VariationId is 93105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000466.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	NM_000466.3	MANE Select	c.2331C>A	p.Gly777Gly	synonymous	Exon 14 of 24	NP_000457.1
	PEX1	NM_001282677.2		c.2160C>A	p.Gly720Gly	synonymous	Exon 13 of 23	NP_001269606.1
	PEX1	NM_001282678.2		c.1707C>A	p.Gly569Gly	synonymous	Exon 14 of 24	NP_001269607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.2331C>A	p.Gly777Gly	synonymous	Exon 14 of 24	ENSP00000248633.4
	PEX1	ENST00000428214.5	TSL:1	c.2160C>A	p.Gly720Gly	synonymous	Exon 13 of 23	ENSP00000394413.1
	PEX1	ENST00000438045.5	TSL:2	c.1365C>A	p.Gly455Gly	synonymous	Exon 11 of 21	ENSP00000410438.1

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141562 AN: 152186 Hom.: 65939 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.913

GnomAD2 exomes AF: 0.921 AC: 231601 AN: 251340 AF XY: 0.920

Gnomad AFR exome AF: 0.976

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.968

Gnomad FIN exome AF: 0.866

Gnomad NFE exome AF: 0.912

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.918 AC: 1341151 AN: 1461244 Hom.: 615917 Cov.: 42 AF XY: 0.918 AC XY: 667282 AN XY: 726982

African (AFR) AF: 0.977 AC: 32690 AN: 33468

American (AMR) AF: 0.940 AC: 42018 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 23724 AN: 26124

East Asian (EAS) AF: 0.964 AC: 38251 AN: 39680

South Asian (SAS) AF: 0.926 AC: 79878 AN: 86236

European-Finnish (FIN) AF: 0.870 AC: 46458 AN: 53416

Middle Eastern (MID) AF: 0.947 AC: 5462 AN: 5768

European-Non Finnish (NFE) AF: 0.915 AC: 1017087 AN: 1111454

Other (OTH) AF: 0.921 AC: 55583 AN: 60376

GnomAD4 genome AF: 0.930 AC: 141681 AN: 152304 Hom.: 65997 Cov.: 32 AF XY: 0.929 AC XY: 69202 AN XY: 74458

African (AFR) AF: 0.976 AC: 40576 AN: 41582

American (AMR) AF: 0.944 AC: 14442 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3146 AN: 3472

East Asian (EAS) AF: 0.967 AC: 5010 AN: 5180

South Asian (SAS) AF: 0.936 AC: 4517 AN: 4828

European-Finnish (FIN) AF: 0.871 AC: 9234 AN: 10602

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61694 AN: 68026

Other (OTH) AF: 0.914 AC: 1933 AN: 2114

Alfa AF: 0.919 Hom.: 36594

Bravo AF: 0.938

Asia WGS AF: 0.943 AC: 3279 AN: 3476

EpiCase AF: 0.911

EpiControl AF: 0.913

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 92% of total chromosomes in ExAC

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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.

Zellweger spectrum disorders Benign:2

Mar 29, 2017

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

Peroxisome biogenesis disorder 1A (Zellweger) Benign:2

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.

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heimler syndrome 1 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Peroxisome biogenesis disorder 1B Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.0
DANN	Benign	0.68
PhyloP100		2.5
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10278857; hg19: chr7-92131289; COSMIC: COSV108017599; COSMIC: COSV108017599;