7-92501975-G-T

Position:

• chr7-92501975-G-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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 -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 id is 93105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92501975-G-T is described in Lovd as [Benign]. Variant chr7-92501975-G-T is described in Lovd as [Pathogenic].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.2331C>A	p.Gly777Gly	synonymous_variant	14/24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.2331C>A	p.Gly777Gly	synonymous_variant	14/24	1	NM_000466.3	ENSP00000248633.4

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

GnomAD3 exomes AF: 0.921 AC: 231601 AN: 251340 Hom.: 106854 AF XY: 0.920 AC XY: 124972 AN XY: 135840

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 SAS exome AF: 0.925

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

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.940

Gnomad4 ASJ exome AF: 0.908

Gnomad4 EAS exome AF: 0.964

Gnomad4 SAS exome AF: 0.926

Gnomad4 FIN exome AF: 0.870

Gnomad4 NFE exome AF: 0.915

Gnomad4 OTH exome AF: 0.921

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

Gnomad4 AFR AF: 0.976

Gnomad4 AMR AF: 0.944

Gnomad4 ASJ AF: 0.906

Gnomad4 EAS AF: 0.967

Gnomad4 SAS AF: 0.936

Gnomad4 FIN AF: 0.871

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.914

Alfa AF: 0.919 Hom.: 36231

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
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: 92% of total chromosomes in ExAC -

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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. -

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	-0.41
CADD	Benign	7.0
DANN	Benign	0.68

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: rs10278857; hg19: chr7-92131289;