1-2412502-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_002617.4(PEX10):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,360,508 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000099 ( 0 hom. )

Consequence

PEX10
NM_002617.4 start_lost

Scores

5
3
8

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.32
Variant links:
Genes affected
PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 29 pathogenic variants. Next in-frame start position is after 432 CDS bases. Genomic position: 2408620. Lost 0.440 part of the original CDS.
PS1
Another start lost variant in NM_002617.4 (PEX10) was described as [Likely_pathogenic] in ClinVar as 3336181
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-2412502-T-C is Pathogenic according to our data. Variant chr1-2412502-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2412502-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PEX10NM_002617.4 linkc.1A>G p.Met1? start_lost Exon 1 of 6 ENST00000447513.7 NP_002608.1 O60683-1A0A024R068

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PEX10ENST00000447513.7 linkc.1A>G p.Met1? start_lost Exon 1 of 6 1 NM_002617.4 ENSP00000407922.2 O60683-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151938
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000993
AC:
12
AN:
1208570
Hom.:
0
Cov.:
31
AF XY:
0.00000678
AC XY:
4
AN XY:
590018
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:
0.0000341
Gnomad4 NFE exome
AF:
0.0000101
Gnomad4 OTH exome
AF:
0.0000203
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
151938
Hom.:
0
Cov.:
34
AF XY:
0.0000539
AC XY:
4
AN XY:
74246
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B Pathogenic:2
May 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 12, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 6A (Zellweger) Pathogenic:1
Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Zellweger spectrum disorders Pathogenic:1
Nov 18, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the PEX10 mRNA. The next in-frame methionine is located at codon 145. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of Zellweger spectrum disorder (PMID: 25179809, 28320181). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280002). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Dec 19, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35038753, 37994247, 28857144, 25179809) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.19
.;T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.083
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Benign
-0.30
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.95
P;B;.
Vest4
0.63
MutPred
0.56
Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);
MVP
0.64
ClinPred
0.99
D
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0
Varity_R
0.95
gMVP
0.55

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.

Other links and lift over

dbSNP: rs886041314; hg19: chr1-2343941; API