rs34154371

Positions:

chr1-2406576-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002617.4(PEX10):c.820A>G(p.Thr274Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,202 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 42 hom., cov: 33)

Exomes 𝑓: 0.023 ( 465 hom. )

Consequence

PEX10
NM_002617.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0106090605).

BP6

Variant 1-2406576-T-C is Benign according to our data. Variant chr1-2406576-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 197887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2406576-T-C is described in Lovd as [Benign]. Variant chr1-2406576-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2850/152162) while in subpopulation NFE AF= 0.0264 (1793/67986). AF 95% confidence interval is 0.0254. There are 42 homozygotes in gnomad4. There are 1323 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX10	NM_002617.4 linkuse as main transcript	c.820A>G	p.Thr274Ala	missense_variant	5/6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 linkuse as main transcript	c.820A>G	p.Thr274Ala	missense_variant	5/6	1	NM_002617.4	ENSP00000407922	P4	O60683-1

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2851

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0842

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00975

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0264

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0203

AC:

5069

AN:

250264

Hom.:

AF XY:

0.0205

AC XY:

2781

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.00428

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0814

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00944

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0231

AC:

33805

AN:

1461040

Hom.:

465

Cov.:

AF XY:

0.0230

AC XY:

16719

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.0824

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0100

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.0248

Gnomad4 OTH exome

AF:

0.0258

GnomAD4 genome

AF:

0.0187

AC:

2850

AN:

152162

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1323

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00472

Gnomad4 AMR

AF:

0.0186

Gnomad4 ASJ

AF:

0.0842

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00976

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.0264

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0270

Hom.:

Bravo

AF:

0.0182

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0286

AC:

246

ExAC

AF:

0.0188

AC:

2277

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0310

EpiControl

AF:

0.0271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13006=2% -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	This variant is associated with the following publications: (PMID: 15542397, 27535533, 19127411) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Peroxisome biogenesis disorder 6A (Zellweger)

Benign:2

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This variant has been identified in >2% of European (non-Finnish) chromosomes and 36 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Zellweger syndrome. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Peroxisome biogenesis disorder, complementation group 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

-0.56

.;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.95

P;D;.

Vest4

0.47

MPC

0.19

ClinPred

0.020

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.44

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

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