rs724160002

Variant names:

• chr1-2412501-A-G
• rs724160002
• NM_002617.4:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-2412501-A-G
• chr1-2412501-A-C
• chr1-2412501-A-T

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_002617.4(PEX10):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,210,336 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 (★★). ClinVar reports functional evidence for this variant: "SCV003845118: PEX10 was defective in fibroblasts from a compound heterozygous patient (with a null variant in trans" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PEX10 NM_002617.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.10
• Publications: 4 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 24 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 145 codons. Genomic position: 2408619. Lost 0.441 part of the original CDS.
• PS1: Another start lost variant in NM_002617.4 (PEX10) was described as [Likely_pathogenic] in ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003845118: PEX10 was defective in fibroblasts from a compound heterozygous patient (with a null variant in trans; Regal_2010).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-2412501-A-G is Pathogenic according to our data. Variant chr1-2412501-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 162434.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.2T>C	p.Met1?	start_lost	Exon 1 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.2T>C	p.Met1?	start_lost	Exon 1 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.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000107 AC: 13 AN: 1210336 Hom.: 0 Cov.: 31 AF XY: 0.00000508 AC XY: 3 AN XY: 590978

African (AFR) AF: 0.00 AC: 0 AN: 24164

American (AMR) AF: 0.00 AC: 0 AN: 13718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18018

East Asian (EAS) AF: 0.00 AC: 0 AN: 26708

South Asian (SAS) AF: 0.00 AC: 0 AN: 53466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.0000131 AC: 13 AN: 992054

Other (OTH) AF: 0.00 AC: 0 AN: 49346

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.010	D
PhyloP100		3.1
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.54
MutPred		0.59		Gain of glycosylation at M1 (P = 0.0074)
MVP		0.80
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.57
Mutation Taster		=3/197	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: rs724160002; hg19: chr1-2343940;