rs9462858

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000287.4(PEX6):c.399G>T(p.Val133Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,535,058 control chromosomes in the GnomAD database, including 145,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12678 hom., cov: 32)

Exomes 𝑓: 0.43 ( 133220 hom. )

Consequence

PEX6
NM_000287.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.405

Variant links:

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 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=-0.64).

BP6

Variant 6-42978752-C-A is Benign according to our data. Variant chr6-42978752-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 92789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978752-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.405 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.399G>T	p.Val133Val	synonymous_variant	1/17	ENST00000304611.13	NP_000278.3	Q13608-1A0A024RD09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 link	c.399G>T	p.Val133Val	synonymous_variant	1/17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.399G>T	p.Val133Val	synonymous_variant	1/15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61088

AN:

151720

Hom.:

12674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.585

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.454

Gnomad OTH

AF:

0.416

GnomAD3 exomes

AF:

0.377

AC:

49572

AN:

131414

Hom.:

10243

AF XY:

0.388

AC XY:

27935

AN XY:

72002

show subpopulations

Gnomad AFR exome

AF:

0.386

Gnomad AMR exome

AF:

0.266

Gnomad ASJ exome

AF:

0.418

Gnomad EAS exome

AF:

0.106

Gnomad SAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.396

Gnomad NFE exome

AF:

0.454

Gnomad OTH exome

AF:

0.415

GnomAD4 exome

AF:

0.434

AC:

600230

AN:

1383220

Hom.:

133220

Cov.:

AF XY:

0.435

AC XY:

296994

AN XY:

682622

show subpopulations

Gnomad4 AFR exome

AF:

0.378

Gnomad4 AMR exome

AF:

0.283

Gnomad4 ASJ exome

AF:

0.414

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.434

Gnomad4 FIN exome

AF:

0.389

Gnomad4 NFE exome

AF:

0.453

Gnomad4 OTH exome

AF:

0.416

GnomAD4 genome

AF:

0.403

AC:

61125

AN:

151838

Hom.:

12678

Cov.:

AF XY:

0.398

AC XY:

29568

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.374

Gnomad4 AMR

AF:

0.339

Gnomad4 ASJ

AF:

0.408

Gnomad4 EAS

AF:

0.103

Gnomad4 SAS

AF:

0.405

Gnomad4 FIN

AF:

0.406

Gnomad4 NFE

AF:

0.454

Gnomad4 OTH

AF:

0.413

Alfa

AF:

0.424

Hom.:

2492

Bravo

AF:

0.394

Asia WGS

AF:

0.260

AC:

905

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2016	Variant summary: The PEX6 c.399G>T (p.Val133Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict the variant not to have a significant impact on splicing. This variant was found in 5625/12518 control chromosomes (1242 homozygotes) at a frequency of 0.4493529, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Heimler syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Peroxisome biogenesis disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Peroxisome biogenesis disorder 4B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.65

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