rs786205656

Variant names:

• chr7-92517854-TTGAC-T
• rs786205656
• NM_000466.3:c.657_660delGTCA

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_660delGTCA​(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 rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.657_660delGTCA	p.Ser220IlefsTer22	frameshift_variant	Exon 5 of 24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.657_660delGTCA	p.Ser220IlefsTer22	frameshift_variant	Exon 5 of 23		NP_001269606.1
PEX1	NM_001282678.2	c.33_36delGTCA	p.Ser12IlefsTer22	frameshift_variant	Exon 5 of 24		NP_001269607.1
PEX1	XM_047420472.1	c.657_660delGTCA	p.Ser220IlefsTer22	frameshift_variant	Exon 5 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.657_660delGTCA	p.Ser220IlefsTer22	frameshift_variant	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4
PEX1	ENST00000428214.5	c.657_660delGTCA	p.Ser220IlefsTer22	frameshift_variant	Exon 5 of 23	1		ENSP00000394413.1
PEX1	ENST00000438045.5	c.274-3891_274-3888delGTCA		intron_variant	Intron 2 of 20	2		ENSP00000410438.1
PEX1	ENST00000484913.5	n.696_699delGTCA		non_coding_transcript_exon_variant	Exon 5 of 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

Feb 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders Pathogenic:1

Nov 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (ExAC no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;