rs786204638

Positions:

• 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	Protein	UniProt
PEX1	NM_000466.3	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23		NP_001269606.1
PEX1	NM_001282678.2	c.287_288del	p.Ser96CysfsTer4	frameshift_variant	5/24		NP_001269607.1
PEX1	XM_047420472.1	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/24	1	NM_000466.3	ENSP00000248633	P1
PEX1	ENST00000428214.5	c.911_912del	p.Ser304CysfsTer4	frameshift_variant	5/23	1		ENSP00000394413
PEX1	ENST00000438045.5	c.274-3637_274-3636del		intron_variant		2		ENSP00000410438
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

Feb 14, 2024

- -

Zellweger spectrum disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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;