rs61752096

Variant names:

• chr1-2406515-C-T
• rs61752096
• NM_002617.4:c.881G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002617.4(PEX10):​c.881G>A​(p.Trp294*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000479 in 1,460,752 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PEX10 NM_002617.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.59
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2406515-C-T is Pathogenic according to our data. Variant chr1-2406515-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2677649.Status of the report is criteria_provided_single_submitter, 1 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.881G>A	p.Trp294*	stop_gained	Exon 5 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.941G>A	p.Trp314*	stop_gained	Exon 5 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.938G>A	p.Trp313*	stop_gained	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.881G>A	p.Trp294*	stop_gained	Exon 5 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.941G>A	p.Trp314*	stop_gained	Exon 5 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.938G>A	p.Trp313*	stop_gained	Exon 5 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250064 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460752 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726720

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Peroxisome biogenesis disorder 6A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		4.6
Vest4		0.54
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61752096; hg19: chr1-2337954;