7-92499783-TACA-T

Position:

• chr7-92499783-TACA-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000248633.9(PEX1):​c.2636_2638del​(p.Leu879del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX1 ENST00000248633.9 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.89

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000248633.9. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-92499783-TACA-T is Pathogenic according to our data. Variant chr7-92499783-TACA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288706.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}. Variant chr7-92499783-TACA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.2636_2638del	p.Leu879del	inframe_deletion	16/24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.2636_2638del	p.Leu879del	inframe_deletion	16/24	1	NM_000466.3	ENSP00000248633	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459646 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726256

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	Apr 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 05, 2018	- -

Zellweger spectrum disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PEX1 protein in which other variant(s) (p.Leu879Ser) have been determined to be pathogenic (PMID: 26287655). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 288706). This variant, c.2636_2638del, results in the deletion of 1 amino acid(s) of the PEX1 protein (p.Leu879del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Zellweger spectrum disorders (PMID: 21031596; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2633_2635delTGT. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886043984; hg19: chr7-92129097;