rs139345520

Variant names:

• chr1-2406811-C-G
• rs139345520
• NM_002617.4:c.685G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002617.4(PEX10):​c.685G>C​(p.Val229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,610,988 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V229A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.780
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011860877).
• BP6: Variant 1-2406811-C-G is Benign according to our data. Variant chr1-2406811-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0062 (944/152338) while in subpopulation AFR AF = 0.0215 (893/41580). AF 95% confidence interval is 0.0203. There are 5 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.685G>C	p.Val229Leu	missense	Exon 4 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.745G>C	p.Val249Leu	missense	Exon 4 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.742G>C	p.Val248Leu	missense	Exon 4 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.685G>C	p.Val229Leu	missense	Exon 4 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.745G>C	p.Val249Leu	missense	Exon 4 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.742G>C	p.Val248Leu	missense	Exon 4 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 943 AN: 152220 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00155 AC: 377 AN: 242962 AF XY: 0.00113

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000730

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000608 AC: 887 AN: 1458650 Hom.: 10 Cov.: 35 AF XY: 0.000521 AC XY: 378 AN XY: 725432

African (AFR) AF: 0.0218 AC: 728 AN: 33442

American (AMR) AF: 0.00108 AC: 48 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52250

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111040

Other (OTH) AF: 0.00133 AC: 80 AN: 60248

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152338 Hom.: 5 Cov.: 34 AF XY: 0.00623 AC XY: 464 AN XY: 74480

African (AFR) AF: 0.0215 AC: 893 AN: 41580

American (AMR) AF: 0.00281 AC: 43 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00700

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00171 AC: 207

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.1
DANN	Benign	0.86
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.40	N
PhyloP100		0.78
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.30
Sift	Benign	0.66	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.59		Loss of MoRF binding (P = 0.0901)
MVP		0.41
MPC		0.092
ClinPred		0.00095	T
GERP RS		2.5
Varity_R		0.072
gMVP		0.46
Mutation Taster		=100/0	polymorphism

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: rs139345520; hg19: chr1-2338250;