rs35830695

Positions:

chr6-42965726-G-A

Variant summary

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

The NM_000287.4(PEX6):c.2426C>T(p.Ala809Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,613,654 control chromosomes in the GnomAD database, including 3,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 503 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2542 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 10.0

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004077047).

BP6

Variant 6-42965726-G-A is Benign according to our data. Variant chr6-42965726-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 167463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42965726-G-A is described in Lovd as [Likely_benign]. Variant chr6-42965726-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.2426C>T	p.Ala809Val	missense_variant	13/17	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.2426C>T	p.Ala809Val	missense_variant	13/17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.2179C>T	p.Pro727Ser	missense_variant	11/15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0718

AC:

10919

AN:

152008

Hom.:

503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0554

Gnomad SAS

AF:

0.0598

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0533

Gnomad OTH

AF:

0.0655

GnomAD3 exomes

AF:

0.0553

AC:

13904

AN:

251470

Hom.:

513

AF XY:

0.0546

AC XY:

7422

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.0332

Gnomad ASJ exome

AF:

0.0450

Gnomad EAS exome

AF:

0.0670

Gnomad SAS exome

AF:

0.0606

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0536

Gnomad OTH exome

AF:

0.0536

GnomAD4 exome

AF:

0.0558

AC:

81539

AN:

1461528

Hom.:

2542

Cov.:

AF XY:

0.0557

AC XY:

40500

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.131

Gnomad4 AMR exome

AF:

0.0346

Gnomad4 ASJ exome

AF:

0.0444

Gnomad4 EAS exome

AF:

0.0639

Gnomad4 SAS exome

AF:

0.0611

Gnomad4 FIN exome

AF:

0.0350

Gnomad4 NFE exome

AF:

0.0547

Gnomad4 OTH exome

AF:

0.0588

GnomAD4 genome

AF:

0.0718

AC:

10928

AN:

152126

Hom.:

503

Cov.:

AF XY:

0.0692

AC XY:

5150

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0406

Gnomad4 ASJ

AF:

0.0461

Gnomad4 EAS

AF:

0.0553

Gnomad4 SAS

AF:

0.0590

Gnomad4 FIN

AF:

0.0344

Gnomad4 NFE

AF:

0.0533

Gnomad4 OTH

AF:

0.0653

Alfa

AF:

0.0563

Hom.:

447

Bravo

AF:

0.0758

TwinsUK

AF:

0.0510

AC:

189

ALSPAC

AF:

0.0545

AC:

210

ESP6500AA

AF:

0.133

AC:

585

ESP6500EA

AF:

0.0535

AC:

460

ExAC

AF:

0.0582

AC:

7069

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

EpiCase

AF:

0.0550

EpiControl

AF:

0.0530

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 11873320, 20981092, 19142205, 27884173, 30245029) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Heimler syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Peroxisome biogenesis disorder

Benign:1

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

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0041

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.86

MPC

0.63

ClinPred

0.040

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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