rs144942544

chr7-92510952-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000466.3(PEX1):c.1579A>G(p.Thr527Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,459,962 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T527T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 1.97

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007453084).
• BP6: Variant 7-92510952-T-C is Benign according to our data. Variant chr7-92510952-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 493456.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=9}. Variant chr7-92510952-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00218 (332/152358) while in subpopulation NFE AF= 0.00362 (246/68032). AF 95% confidence interval is 0.00324. There are 1 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.1579A>G	p.Thr527Ala	missense_variant	8/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.1579A>G	p.Thr527Ala	missense_variant	8/24	1	NM_000466.3	P1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00206 AC: 512 AN: 248932 Hom.: 0 AF XY: 0.00222 AC XY: 299 AN XY: 134948

Gnomad AFR exome AF: 0.000515

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00159

Gnomad FIN exome AF: 0.000833

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00249 AC: 3260 AN: 1307604 Hom.: 6 Cov.: 21 AF XY: 0.00249 AC XY: 1643 AN XY: 658608

Gnomad4 AFR exome AF: 0.000393

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.000657

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00256

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00197 AC XY: 147 AN XY: 74504

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00362

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00327 Hom.: 1

Bravo AF: 0.00240

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000467 AC: 2

ESP6500EA AF: 0.00342 AC: 29

ExAC AF: 0.00201 AC: 244

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PEX1: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PEX1 p.Thr527Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs144942544), ClinVar (classified as likely benign by EGL Genetic Diagnostics and as a VUS by Mayo Clinic Genetic Testing Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 587 of 280334 chromosomes at a frequency of 0.002094 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 458 of 128286 chromosomes (freq: 0.00357), Other in 13 of 7140 chromosomes (freq: 0.001821), South Asian in 48 of 30138 chromosomes (freq: 0.001593), Latino in 32 of 35238 chromosomes (freq: 0.000908), European (Finnish) in 19 of 25088 chromosomes (freq: 0.000757) and African in 17 of 24248 chromosomes (freq: 0.000701); it was not observed in the Ashkenazi Jewish, and East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr527 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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	-	- -

Peroxisome biogenesis disorder 1B Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2016	- -

Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2019	Variant summary: PEX1 c.1579A>G (p.Thr527Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 248932 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.0021 vs 0.0039). However, this frequency is significantly higher than the frequency of the most common pathogenic variant in PEX1 (c.2097dupT/p.Ile700TyrfsTer42, 0.00048 in gnomAD), suggesting the variant of interest is unlikely to be pathogenic. c.1579A>G has been reported in the literature in individuals affected with Zellweger Syndrome and retinal dystrophy without specified allele in trans (Ebberink_2010, Watson_2014). These reports do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (1x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2016	- -

Zellweger spectrum disorders Benign:2

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

PEX1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Heimler syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	0.89	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.17	.;B;.
Vest4		0.17
MVP		0.78
MPC		0.18
ClinPred		0.017	T
GERP RS		0.89
Varity_R		0.045
gMVP		0.37

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: rs144942544; hg19: chr7-92140266;