rs61750434

Variant names:

• chr1-2408679-G-A
• rs61750434
• NM_002617.4:c.373C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-2408679-G-A
• chr1-2408679-G-C

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.373C>T​(p.Arg125*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,386 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PEX10 NM_002617.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0910
• 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 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 1-2408679-G-A is Pathogenic according to our data. Variant chr1-2408679-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6772.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.373C>T	p.Arg125*	stop_gained	Exon 3 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.373C>T	p.Arg125*	stop_gained	Exon 3 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.373C>T	p.Arg125*	stop_gained	Exon 3 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.373C>T	p.Arg125*	stop_gained	Exon 3 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.373C>T	p.Arg125*	stop_gained	Exon 3 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.373C>T	p.Arg125*	stop_gained	Exon 3 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460200 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726414

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111444

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
PhyloP100		0.091
Vest4		0.72
GERP RS		-1.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61750434; hg19: chr1-2340118; COSMIC: COSV99992173; COSMIC: COSV99992173;