rs786204638

chr7-92517602-CAG-C

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.911_912del(p.Ser304CysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PEX1 NM_000466.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.71

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 7-92517602-CAG-C is Pathogenic according to our data. Variant chr7-92517602-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517602-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/24	ENST00000248633.9
PEX1	NM_001282677.2	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23
PEX1	NM_001282678.2	c.287_288del	p.Ser96CysfsTer4	frameshift_variant	5/24
PEX1	XM_047420472.1	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/24	1	NM_000466.3	P1
PEX1	ENST00000428214.5	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23	1
PEX1	ENST00000438045.5	c.274-3637_274-3636del		intron_variant		2
PEX1	ENST00000484913.5	n.950_951del		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 13, 2023

- -

Zellweger spectrum disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189029). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum condition(s) (PMID: 16141001). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser304Cysfs*4) 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). -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Oct 21, 2014

- -

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: rs786204638; hg19: chr7-92146916;