rs724160000

Variant names:

• chr1-2406566-A-G
• rs724160000
• NM_002617.4:c.830T>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002617.4(PEX10):​c.830T>C​(p.Leu277Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,048 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. L277L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 6.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 38) in uniprot entity PEX10_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002617.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 1-2406566-A-G is Pathogenic according to our data. Variant chr1-2406566-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4	c.830T>C	p.Leu277Pro	missense_variant	Exon 5 of 6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.830T>C	p.Leu277Pro	missense_variant	Exon 5 of 6	1	NM_002617.4	ENSP00000407922.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461048 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B Pathogenic:2 Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PM3_Strong+PP4 -

Mar 08, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 6A (Zellweger) Pathogenic:1

Jan 03, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 6B Pathogenic:1

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Peroxisome biogenesis disorder, complementation group 7 Pathogenic:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 297 of the PEX10 protein (p.Leu297Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with peroxisomal biogenesis disorders (PMID: 19127411, 30640048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 162432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PEX10 function (PMID: 26319495). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Jun 17, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.71		.;Gain of disorder (P = 0.0229);Gain of disorder (P = 0.0229);
MVP		0.98
MPC		0.63
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.90

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: rs724160000; hg19: chr1-2338005;