NM_002617.4:c.730C>T

Variant names:

• chr1-2406766-G-A
• rs61752092
• NM_002617.4:c.730C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002617.4(PEX10):​c.730C>T​(p.Arg244*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,456,660 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PEX10 NM_002617.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.27
• 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: Ambry Genetics, G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, 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 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 1-2406766-G-A is Pathogenic according to our data. Variant chr1-2406766-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 162435.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	NM_002617.4	MANE Select	c.730C>T	p.Arg244*	stop_gained	Exon 4 of 6	NP_002608.1
	PEX10	NM_153818.2		c.790C>T	p.Arg264*	stop_gained	Exon 4 of 6	NP_722540.1
	PEX10	NM_001374425.1		c.787C>T	p.Arg263*	stop_gained	Exon 4 of 6	NP_001361354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	ENST00000447513.7	TSL:1 MANE Select	c.730C>T	p.Arg244*	stop_gained	Exon 4 of 6	ENSP00000407922.2
	PEX10	ENST00000288774.8	TSL:1	c.790C>T	p.Arg264*	stop_gained	Exon 4 of 6	ENSP00000288774.3
	PEX10	ENST00000874692.1		c.787C>T	p.Arg263*	stop_gained	Exon 4 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000253 AC: 6 AN: 237538 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456660 Hom.: 0 Cov.: 35 AF XY: 0.00000828 AC XY: 6 AN XY: 724288

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.0000907 AC: 4 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110442

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 34

Alfa AF: 0.000507 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Peroxisome biogenesis disorder 6A (Zellweger) (2)
1	-	-	Peroxisome biogenesis disorder (1)
1	-	-	Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B (1)
1	-	-	Peroxisome biogenesis disorder 6B (1)
1	-	-	Peroxisome biogenesis disorder, complementation group 7 (1)
1	-	-	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		2.3
Vest4		0.60
GERP RS		5.0
Mutation Taster		=9/191	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: rs61752092; hg19: chr1-2338205;