rs35830695

Positions:

• chr6-42965726-G-A

Variant summary

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

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 10.0

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]

ACMG classification

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	UniProt
PEX6	NM_000287.4	c.2426C>T	p.Ala809Val	missense_variant	13/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.2426C>T	p.Ala809Val	missense_variant	13/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.2179C>T	p.Pro727Ser	missense_variant	11/15	1

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10919 AN: 152008 Hom.: 503 Cov.: 32

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

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.: 33 AF XY: 0.0557 AC XY: 40500 AN XY: 727084

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.: 32 AF XY: 0.0692 AC XY: 5150 AN XY: 74376

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 11873320, 20981092, 19142205, 27884173, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -

not specified Benign:3

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2021	- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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

Invitae

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	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	8.8e-11	P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.86
MPC		0.63
ClinPred		0.040	T
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

Other links and lift over

dbSNP: rs35830695; hg19: chr6-42933464; COSMIC: COSV55102348; COSMIC: COSV55102348;