12-7202673-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001351132.2(PEX5):c.815T>C(p.Met272Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,998 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 83 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 97 hom. )

Consequence

PEX5
NM_001351132.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

PEX5 (HGNC:9719): (peroxisomal biogenesis factor 5) The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

PEX5 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=0.0031735003).

BP6

Variant 12-7202673-T-C is Benign according to our data. Variant chr12-7202673-T-C is described in ClinVar as [Benign]. Clinvar id is 235376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5	NM_001351132.2 link	c.815T>C	p.Met272Thr	missense_variant	Exon 9 of 16	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1 link	c.815T>C	p.Met272Thr	missense_variant	Exon 9 of 16		NM_001351132.2	ENSP00000502374.1		P50542-1

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3109

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00548

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00746

AC:

1877

AN:

251494

Hom.:

AF XY:

0.00608

AC XY:

827

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00570

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00573

AC:

8372

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

3918

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0587

Gnomad4 AMR exome

AF:

0.00474

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.00492

Gnomad4 OTH exome

AF:

0.00695

GnomAD4 genome

AF:

0.0205

AC:

3121

AN:

152200

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1500

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0610

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00548

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.00775

Hom.:

Bravo

AF:

0.0231

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.0531

AC:

234

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00876

AC:

1063

EpiCase

AF:

0.00436

EpiControl

AF:

0.00492

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 2B

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 2B;C3550273:Peroxisome biogenesis disorder 2A (Zellweger);C4225237:Rhizomelic chondrodysplasia punctata type 5

Benign:1

Nov 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 2A (Zellweger)

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.18

T;.;.;.;T;T;T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.58

.;T;T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

N;.;.;.;N;.;.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.22

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.42

T;T;T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;B;B;.;B

Vest4

0.27

MVP

0.78

MPC

0.31

ClinPred

0.0016

GERP RS

4.5

Varity_R

0.022

gMVP

0.33

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