rs146452560

Variant names:

• chr1-2408734-C-T
• rs146452560
• NM_002617.4:c.318G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2408734-C-T
• chr1-2408734-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002617.4(PEX10):​c.318G>A​(p.Leu106Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00968 in 1,613,844 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L106L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: PEX10 NM_002617.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0950
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-2408734-C-T is Benign according to our data. Variant chr1-2408734-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.095 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00634 (966/152292) while in subpopulation NFE AF = 0.0106 (721/68010). AF 95% confidence interval is 0.00996. There are 7 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.318G>A	p.Leu106Leu	synonymous	Exon 3 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.318G>A	p.Leu106Leu	synonymous	Exon 3 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.318G>A	p.Leu106Leu	synonymous	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.318G>A	p.Leu106Leu	synonymous	Exon 3 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.318G>A	p.Leu106Leu	synonymous	Exon 3 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.318G>A	p.Leu106Leu	synonymous	Exon 3 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.00635 AC: 966 AN: 152174 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00640 AC: 1601 AN: 250084 AF XY: 0.00615

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00359

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00590

GnomAD4 exome AF: 0.0100 AC: 14649 AN: 1461552 Hom.: 98 Cov.: 32 AF XY: 0.00970 AC XY: 7053 AN XY: 727108

African (AFR) AF: 0.00149 AC: 50 AN: 33478

American (AMR) AF: 0.00333 AC: 149 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86254

European-Finnish (FIN) AF: 0.00642 AC: 342 AN: 53274

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0120 AC: 13380 AN: 1111902

Other (OTH) AF: 0.00841 AC: 508 AN: 60378

GnomAD4 genome AF: 0.00634 AC: 966 AN: 152292 Hom.: 7 Cov.: 33 AF XY: 0.00590 AC XY: 439 AN XY: 74468

African (AFR) AF: 0.00224 AC: 93 AN: 41556

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.00583 AC: 62 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0106 AC: 721 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00765 Hom.: 5

Bravo AF: 0.00621

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder 6A (Zellweger) (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_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.84
PhyloP100		0.095
Mutation Taster		=98/2	polymorphism

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: rs146452560; hg19: chr1-2340173; COSMIC: COSV56580136; COSMIC: COSV56580136;