rs145430946

Variant names:

• chr7-92501648-G-A
• rs145430946
• NM_000466.3:c.2442C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-92501648-G-A
• chr7-92501648-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000466.3(PEX1):​c.2442C>T​(p.Phe814Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,613,742 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (14 hom.)
• Consequence: PEX1 NM_000466.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.62
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 7-92501648-G-A is Benign according to our data. Variant chr7-92501648-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93106.
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00228 (347/152224) while in subpopulation NFE AF = 0.0034 (231/68012). AF 95% confidence interval is 0.00304. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.2442C>T	p.Phe814Phe	synonymous_variant	Exon 15 of 24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.2442C>T	p.Phe814Phe	synonymous_variant	Exon 15 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00236 AC: 593 AN: 251264 AF XY: 0.00254

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00289 AC: 4219 AN: 1461518 Hom.: 14 Cov.: 31 AF XY: 0.00291 AC XY: 2117 AN XY: 727090

African (AFR) AF: 0.00122 AC: 41 AN: 33470

American (AMR) AF: 0.00233 AC: 104 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86248

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53412

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5766

European-Non Finnish (NFE) AF: 0.00306 AC: 3403 AN: 1111706

Other (OTH) AF: 0.00373 AC: 225 AN: 60380

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74422

African (AFR) AF: 0.000770 AC: 32 AN: 41546

American (AMR) AF: 0.00301 AC: 46 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4814

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00340 AC: 231 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00272 Hom.: 0

Bravo AF: 0.00252

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PEX1: BP4, BP7 -

not specified Benign:2

Jun 06, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PEX1 c.2442C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0024 in 251264 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is comparable to the estimated maximal expected allele frequency for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.0039), suggesting this is likely a benign polymorphism. To our knowledge, no occurrence of c.2442C>T in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and once as uncertain significance. An additional submitter (evaluation in 2013) cites the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders Benign:2

May 10, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs145430946; hg19: chr7-92130962; COSMIC: COSV104373605;