Genetic Variant NM_000466.3:c.569C>A (chr7-92517946-G-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000466.3(PEX1):c.569C>A(p.Ser190*) 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 (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.73

Variant links:

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]

PEX1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.569C>A	p.Ser190*	stop_gained	Exon 5 of 24	ENST00000248633.9	NP_000457.1	O43933-1
PEX1	NM_001282677.2 link	c.569C>A	p.Ser190*	stop_gained	Exon 5 of 23		NP_001269606.1	O43933A0A0C4DG33
PEX1	XM_047420472.1 link	c.569C>A	p.Ser190*	stop_gained	Exon 5 of 23		XP_047276428.1
PEX1	NM_001282678.2 link	c.-56C>A		5_prime_UTR_variant	Exon 5 of 24		NP_001269607.1	O43933B4DER6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PEX1	ENST00000248633.9 link	c.569C>A	p.Ser190*	stop_gained	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4	O43933-1
PEX1	ENST00000428214.5 link	c.569C>A	p.Ser190*	stop_gained	Exon 5 of 23	1		ENSP00000394413.1	A0A0C4DG33
PEX1	ENST00000438045.5 link	c.274-3979C>A		intron_variant	Intron 2 of 20	2		ENSP00000410438.1	O43933-2
PEX1	ENST00000484913.5 link	n.608C>A		non_coding_transcript_exon_variant	Exon 5 of 24	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718280

show subpopulations

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Pathogenic:2

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2019

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.Ser190*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). 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). 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. -

Peroxisome biogenesis disorder 1A (Zellweger)

Pathogenic:1

Mar 08, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.25

Eigen_PC

Benign

-0.030

FATHMM_MKL

Uncertain

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over