rs61736380

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The NM_002617.4(PEX10):c.712G>C(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,610,650 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G238S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

PEX10
NM_002617.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.469

Variant links:

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 links:

PEX10 (HGNC:):

PEX10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 89) in uniprot entity PEX10_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_002617.4

BP4

Computational evidence support a benign effect (MetaRNN=0.010670394).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152332) while in subpopulation NFE AF= 0.00209 (142/68030). AF 95% confidence interval is 0.00181. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX10	NM_002617.4 linkuse as main transcript	c.712G>C	p.Gly238Arg	missense_variant	4/6	ENST00000447513.7	NP_002608.1	O60683-1A0A024R068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 linkuse as main transcript	c.712G>C	p.Gly238Arg	missense_variant	4/6	1	NM_002617.4	ENSP00000407922.2		O60683-1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00129

AC:

312

AN:

241814

Hom.:

AF XY:

0.00136

AC XY:

179

AN XY:

131790

show subpopulations

Gnomad AFR exome

AF:

0.000266

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00194

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS exome

AF:

0.000401

Gnomad FIN exome

AF:

0.000196

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.00113

AC:

1643

AN:

1458318

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

844

AN XY:

725264

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00142

Gnomad4 ASJ exome

AF:

0.00215

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000513

Gnomad4 FIN exome

AF:

0.000326

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.00153

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152332

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00116

AC:

141

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger)

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2023	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2018	- -

Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

PEX10-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Peroxisome biogenesis disorder, complementation group 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Zellweger spectrum disorders

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;T

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.2

N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.82

P;P;.

Vest4

0.31

MVP

0.84

MPC

0.22

ClinPred

0.038

GERP RS

-0.23

Varity_R

0.058

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over