rs76708142

chr12-7202673-T-Cchr12-7202673-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.46

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]

ACMG classification

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/exons	MANE	UniProt
PEX5	NM_001351132.2	c.815T>C	p.Met272Thr	missense_variant	9/16	ENST00000675855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX5	ENST00000675855.1	c.815T>C	p.Met272Thr	missense_variant	9/16		NM_001351132.2	A1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152082 Hom.: 81 Cov.: 32

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.: 35 AF XY: 0.00608 AC XY: 827 AN XY: 135922

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.: 97 Cov.: 31 AF XY: 0.00539 AC XY: 3918 AN XY: 727200

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.: 83 Cov.: 32 AF XY: 0.0202 AC XY: 1500 AN XY: 74406

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.: 15

Bravo AF: 0.0231

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.0531 AC: 234

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00876 AC: 1063

EpiCase AF: 0.00436

EpiControl AF: 0.00492

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -

Peroxisome biogenesis disorder 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Peroxisome biogenesis disorder 2B;C3550273:Peroxisome biogenesis disorder 2A (Zellweger);C4225237:Rhizomelic chondrodysplasia punctata type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 16, 2021

- -

Peroxisome biogenesis disorder 2A (Zellweger) Benign:1

Benign, 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 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	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	12
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	D
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N;.;.;.;N;.;.;N
MutationTaster	Benign	0.96	N;N;N;N;N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs76708142; hg19: chr12-7355269;