6-42964464-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000287.4(PEX6):c.2814G>A(p.Glu938Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,612,222 control chromosomes in the GnomAD database, including 227,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24877 hom., cov: 33)

Exomes 𝑓: 0.52 ( 202631 hom. )

Consequence

PEX6
NM_000287.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.520

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 6-42964464-C-T is Benign according to our data. Variant chr6-42964464-C-T is described in ClinVar as [Benign]. Clinvar id is 92786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42964464-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.2814G>A	p.Glu938Glu	synonymous_variant	Exon 17 of 17	ENST00000304611.13	NP_000278.3	Q13608-1A0A024RD09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 link	c.2814G>A	p.Glu938Glu	synonymous_variant	Exon 17 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546 link	c.*350G>A		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.558

AC:

84663

AN:

151794

Hom.:

24839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.535

Gnomad OTH

AF:

0.551

GnomAD3 exomes

AF:

0.476

AC:

118313

AN:

248410

Hom.:

30370

AF XY:

0.484

AC XY:

65166

AN XY:

134716

show subpopulations

Gnomad AFR exome

AF:

0.735

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.194

Gnomad SAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.456

Gnomad NFE exome

AF:

0.530

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.520

AC:

760079

AN:

1460310

Hom.:

202631

Cov.:

AF XY:

0.521

AC XY:

378761

AN XY:

726500

show subpopulations

Gnomad4 AFR exome

AF:

0.738

Gnomad4 AMR exome

AF:

0.330

Gnomad4 ASJ exome

AF:

0.466

Gnomad4 EAS exome

AF:

0.205

Gnomad4 SAS exome

AF:

0.522

Gnomad4 FIN exome

AF:

0.454

Gnomad4 NFE exome

AF:

0.537

Gnomad4 OTH exome

AF:

0.515

GnomAD4 genome

AF:

0.558

AC:

84754

AN:

151912

Hom.:

24877

Cov.:

AF XY:

0.549

AC XY:

40736

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.732

Gnomad4 AMR

AF:

0.418

Gnomad4 ASJ

AF:

0.465

Gnomad4 EAS

AF:

0.182

Gnomad4 SAS

AF:

0.491

Gnomad4 FIN

AF:

0.462

Gnomad4 NFE

AF:

0.535

Gnomad4 OTH

AF:

0.547

Alfa

AF:

0.548

Hom.:

11623

Bravo

AF:

0.562

Asia WGS

AF:

0.353

AC:

1231

AN:

3478

EpiCase

AF:

0.539

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 10, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX6 c.2814G>A (p.Glu938Glu) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may alter ESE binding. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 58981/120096 (15519 homozygotes, 1/2), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PEX6 variant of 1/516 (0.0019365), suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign." Therefore, the variant of interest has been classified as Benign. -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:2

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Heimler syndrome 2

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4B

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.3

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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