rs61752093

Variant names:

• chr1-2406580-CAG-C
• rs61752093
• NM_002617.4:c.814_815delCT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_002617.4(PEX10):​c.814_815delCT​(p.Leu272ValfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000355604: In vivo complementation analyses in patient fibroblasts demonstrated that the p.Leu292ValfsTer66 variant results in a deficiency in PEX10 protein activity (Okumoto et al. 1998)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L272L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: PEX10 NM_002617.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 0.566
• Publications: 5 publications found

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]

PEX10 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 6A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Ambry Genetics, G2P
• peroxisome biogenesis disorder 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive ataxia due to PEX10 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000355604: In vivo complementation analyses in patient fibroblasts demonstrated that the p.Leu292ValfsTer66 variant results in a deficiency in PEX10 protein activity (Okumoto et al. 1998).; SCV000699965: At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. PMID: 21031596, 9371928, 12794690, 10862081; SCV002571122: Published functional studies demonstrated a loss of PEX10 activity in an in vitro assay, suggesting a damaging effect (PMID: 10862081); SCV000940625: Experimental studies have shown that this premature translational stop signal affects PEX10 function (PMID: 9700193, 10862081).
• PP5: Variant 1-2406580-CAG-C is Pathogenic according to our data. Variant chr1-2406580-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 296273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002617.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	NM_002617.4	MANE Select	c.814_815delCT	p.Leu272ValfsTer66	frameshift	Exon 5 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.874_875delCT	p.Leu292ValfsTer66	frameshift	Exon 5 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.871_872delCT	p.Leu291ValfsTer66	frameshift	Exon 5 of 6	NP_001361354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	ENST00000447513.7	TSL:1 MANE Select	c.814_815delCT	p.Leu272ValfsTer66	frameshift	Exon 5 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.874_875delCT	p.Leu292ValfsTer66	frameshift	Exon 5 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.871_872delCT	p.Leu291ValfsTer66	frameshift	Exon 5 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000360 AC: 9 AN: 250340 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461110 Hom.: 0 AF XY: 0.0000316 AC XY: 23 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Peroxisome biogenesis disorder 6A (Zellweger) (4)
3	-	-	not provided (3)
1	-	-	Peroxisome biogenesis disorder (2)
1	-	-	Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B (1)
1	-	-	Peroxisome biogenesis disorder 6B (2)
1	-	-	Peroxisome biogenesis disorder, complementation group 7 (1)
1	-	-	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61752093; hg19: chr1-2338019;