rs35996821

chr7-92503179-T-C

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.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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I696V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1011 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0440

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 (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	UniProt
PEX1	NM_000466.3	c.2088A>G	p.Ile696Met	missense_variant	13/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.2088A>G	p.Ile696Met	missense_variant	13/24	1	NM_000466.3	P1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3868 AN: 152178 Hom.: 57 Cov.: 32

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

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.: 31 AF XY: 0.0346 AC XY: 25173 AN XY: 726872

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.: 56 Cov.: 32 AF XY: 0.0247 AC XY: 1836 AN XY: 74464

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: 36

ESP6500EA AF: 0.0402 AC: 346

ExAC AF: 0.0267 AC: 3238

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0445

EpiControl AF: 0.0411

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:3

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	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	- -
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. -

Zellweger spectrum disorders Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	10
Dann	Benign	0.61
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.83	D;D;D;N
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs35996821; hg19: chr7-92132493; COSMIC: COSV104373578; COSMIC: COSV104373578;