rs145430946

chr7-92501648-G-Achr7-92501648-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_000466.3(PEX1):c.2442C>T(p.Phe814=) 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

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 -8 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 id is 93106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr7-92501648-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.2442C>T	p.Phe814=	synonymous_variant	15/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.2442C>T	p.Phe814=	synonymous_variant	15/24	1	NM_000466.3	P1

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

GnomAD3 exomes AF: 0.00236 AC: 593 AN: 251264 Hom.: 0 AF XY: 0.00254 AC XY: 345 AN XY: 135828

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 SAS exome AF: 0.00238

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

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00373

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

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00287 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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PEX1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -

Zellweger spectrum disorders Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1

Uncertain significance, 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, 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs145430946; hg19: chr7-92130962; COSMIC: COSV104373605; COSMIC: COSV104373605;