chr12-7209754-G-A

Position:

chr12-7209754-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001351132.2(PEX5):c.1632G>A(p.Ala544=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,571,076 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0080 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 8 hom. )

Consequence

PEX5
NM_001351132.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -8.53

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 12-7209754-G-A is Benign according to our data. Variant chr12-7209754-G-A is described in ClinVar as [Benign]. Clinvar id is 257546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.53 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (950/119090) while in subpopulation AFR AF= 0.0272 (883/32448). AF 95% confidence interval is 0.0257. There are 8 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX5	NM_001351132.2 linkuse as main transcript	c.1632G>A	p.Ala544=	synonymous_variant	15/16	ENST00000675855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX5	ENST00000675855.1 linkuse as main transcript	c.1632G>A	p.Ala544=	synonymous_variant	15/16		NM_001351132.2	A1	P50542-1

Frequencies

GnomAD3 genomes

AF:

0.00803

AC:

956

AN:

119014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00261

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00102

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000129

Gnomad MID

AF:

0.00382

Gnomad NFE

AF:

0.000312

Gnomad OTH

AF:

0.00954

GnomAD3 exomes

AF:

0.00197

AC:

496

AN:

251466

Hom.:

AF XY:

0.00141

AC XY:

192

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0235

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000909

AC:

1320

AN:

1451986

Hom.:

Cov.:

AF XY:

0.000777

AC XY:

561

AN XY:

722322

show subpopulations

Gnomad4 AFR exome

AF:

0.0220

Gnomad4 AMR exome

AF:

0.00185

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000283

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000228

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00798

AC:

950

AN:

119090

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

482

AN XY:

57880

show subpopulations

Gnomad4 AFR

AF:

0.0272

Gnomad4 AMR

AF:

0.00252

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00103

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000129

Gnomad4 NFE

AF:

0.000312

Gnomad4 OTH

AF:

0.00939

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00695

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Peroxisome biogenesis disorder 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.042

DANN

Benign

0.58

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