rs786205656

Positions:

• chr7-92517854-TTGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000466.3(PEX1):​c.657_660del​(p.Ser220IlefsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 NM_000466.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.18

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92517854-TTGAC-T is Pathogenic according to our data. Variant chr7-92517854-TTGAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517854-TTGAC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.657_660del	p.Ser220IlefsTer22	frameshift_variant	5/24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.657_660del	p.Ser220IlefsTer22	frameshift_variant	5/23		NP_001269606.1
PEX1	NM_001282678.2	c.33_36del	p.Ser12IlefsTer22	frameshift_variant	5/24		NP_001269607.1
PEX1	XM_047420472.1	c.657_660del	p.Ser220IlefsTer22	frameshift_variant	5/23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.657_660del	p.Ser220IlefsTer22	frameshift_variant	5/24	1	NM_000466.3	ENSP00000248633	P1
PEX1	ENST00000428214.5	c.657_660del	p.Ser220IlefsTer22	frameshift_variant	5/23	1		ENSP00000394413
PEX1	ENST00000438045.5	c.274-3891_274-3888del		intron_variant		2		ENSP00000410438
PEX1	ENST00000484913.5	n.696_699del		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heimler syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 17, 2024

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Zellweger spectrum disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 191337). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser220Ilefs*22) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

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: rs786205656; hg19: chr7-92147168;