rs35996821

Positions:

chr7-92503179-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000466.3(PEX1):c.2088A>G(p.Ile696Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,270 control chromosomes in the GnomAD database, including 1,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 56 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1011 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0440

Variant links:

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 links:

PEX1 (HGNC:):

PEX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003272444).

BP6

Variant 7-92503179-T-C is Benign according to our data. Variant chr7-92503179-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92503179-T-C is described in Lovd as [Benign]. Variant chr7-92503179-T-C is described in Lovd as [Likely_benign]. Variant chr7-92503179-T-C is described in Lovd as [Pathogenic].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3 linkuse as main transcript	c.2088A>G	p.Ile696Met	missense_variant	13/24	ENST00000248633.9	NP_000457.1	O43933-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 linkuse as main transcript	c.2088A>G	p.Ile696Met	missense_variant	13/24	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3868

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00736

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0387

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0271

AC:

6802

AN:

251034

Hom.:

117

AF XY:

0.0283

AC XY:

3836

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00646

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.0425

Gnomad EAS exome

AF:

0.00365

Gnomad SAS exome

AF:

0.0211

Gnomad FIN exome

AF:

0.0235

Gnomad NFE exome

AF:

0.0382

Gnomad OTH exome

AF:

0.0327

GnomAD4 exome

AF:

0.0348

AC:

50800

AN:

1460974

Hom.:

1011

Cov.:

AF XY:

0.0346

AC XY:

25173

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00666

Gnomad4 AMR exome

AF:

0.0161

Gnomad4 ASJ exome

AF:

0.0402

Gnomad4 EAS exome

AF:

0.00315

Gnomad4 SAS exome

AF:

0.0214

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0389

Gnomad4 OTH exome

AF:

0.0345

GnomAD4 genome

AF:

0.0254

AC:

3865

AN:

152296

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1836

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00734

Gnomad4 AMR

AF:

0.0216

Gnomad4 ASJ

AF:

0.0378

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.0182

Gnomad4 FIN

AF:

0.0221

Gnomad4 NFE

AF:

0.0386

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0362

Hom.:

161

Bravo

AF:

0.0260

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0314

AC:

121

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0402

AC:

346

ExAC

AF:

0.0267

AC:

3238

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0445

EpiControl

AF:

0.0411

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:3

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Peroxisome biogenesis disorder 1A (Zellweger), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BA1 => Allele frequency is >2% in Exome Aggregation Consortium (in some populations allele frequency is >4%). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
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	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.29

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.66

.;N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.60

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.044

MPC

0.17

ClinPred

0.0043

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over