rs1554375599

Positions:

• chr7-92517946-G-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.569C>A​(p.Ser190Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S190S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PEX1 NM_000466.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.73

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 7-92517946-G-T is Pathogenic according to our data. Variant chr7-92517946-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517946-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.569C>A	p.Ser190Ter	stop_gained	5/24	ENST00000248633.9
PEX1	NM_001282677.2	c.569C>A	p.Ser190Ter	stop_gained	5/23
PEX1	XM_047420472.1	c.569C>A	p.Ser190Ter	stop_gained	5/23
PEX1	NM_001282678.2	c.-56C>A		5_prime_UTR_variant	5/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.569C>A	p.Ser190Ter	stop_gained	5/24	1	NM_000466.3	P1
PEX1	ENST00000428214.5	c.569C>A	p.Ser190Ter	stop_gained	5/23	1
PEX1	ENST00000438045.5	c.274-3979C>A		intron_variant		2
PEX1	ENST00000484913.5	n.608C>A		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445618 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718280

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Zellweger spectrum disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2019	Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals affected with Zellweger syndrome spectrum disorder (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 551013). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser190*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.40
GERP RS		3.5

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: rs1554375599; hg19: chr7-92147260;