rs200752969

Positions:

• chr7-92517888-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PVS1 PM2 BP6 BS1

The NM_001282678.2(PEX1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,548,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PEX1 NM_001282678.2 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:2
• Conservation: PhyloP100: -0.197

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-92517888-C-T is Benign according to our data. Variant chr7-92517888-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000112 (156/1395800) while in subpopulation MID AF= 0.0037 (20/5412). AF 95% confidence interval is 0.00245. There are 0 homozygotes in gnomad4_exome. There are 78 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.627G>A	p.Met209Ile	missense_variant	5/24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282678.2	c.3G>A	p.Met1?	start_lost	5/24		NP_001269607.1
PEX1	NM_001282677.2	c.627G>A	p.Met209Ile	missense_variant	5/23		NP_001269606.1
PEX1	XM_047420472.1	c.627G>A	p.Met209Ile	missense_variant	5/23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.627G>A	p.Met209Ile	missense_variant	5/24	1	NM_000466.3	ENSP00000248633.4
PEX1	ENST00000428214.5	c.627G>A	p.Met209Ile	missense_variant	5/23	1		ENSP00000394413.1
PEX1	ENST00000438045.5	c.274-3921G>A		intron_variant		2		ENSP00000410438.1
PEX1	ENST00000484913.5	n.666G>A		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000209 AC: 41 AN: 196000 Hom.: 0 AF XY: 0.000219 AC XY: 23 AN XY: 105016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000481

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 156 AN: 1395800 Hom.: 0 Cov.: 33 AF XY: 0.000113 AC XY: 78 AN XY: 689056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000475

Gnomad4 ASJ exome AF: 0.000924

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000955

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000783

Gnomad4 OTH exome AF: 0.000157

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2023	BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1 Uncertain:2

Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2018	- -
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 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2024	Variant summary: PEX1 c.627G>A (p.Met209Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 196000 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.00021 vs 0.0039; gnomAD v2), allowing no conclusion about variant significance. c.627G>A has been reported in the literature in at least one individual affected with Zellweger spectrum disorder in a homozygous individual from a consanguieous Saudi Arabian family (e.g. Alfares_2017). However, the frequency of the variant in control chromosomes in the Middle Eastern subpopulation was measured at 0.003505 in 5706 chromosomes (gnomAD v4), therefore, this report does 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. The following publications have been ascertained in the context of this evaluation (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 167445). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

Zellweger spectrum disorders Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 18, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.627G>A (p.M209I) alteration is located in exon 5 (coding exon 5) of the PEX1 gene. This alteration results from a G to A substitution at nucleotide position 627, causing the methionine (M) at amino acid position 209 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Heimler syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 10, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.57
DANN	Benign	0.51
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.15
Sift	Benign	0.18	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0010	B;.
Vest4		0.045
MutPred		0.33		Gain of catalytic residue at M209 (P = 0.0142);Gain of catalytic residue at M209 (P = 0.0142);
MVP		0.56
MPC		0.18
ClinPred		0.013	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.18

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: rs200752969; hg19: chr7-92147202;