rs9462858

chr6-42978752-C-Achr6-42978752-C-Gchr6-42978752-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000287.4(PEX6):c.399G>T(p.Val133=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (12678 hom., cov: 32)
  • Exomes 𝑓: 0.43 (133220 hom.)
• Consequence: PEX6 NM_000287.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.405

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 -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	UniProt
PEX6	NM_000287.4	c.399G>T	p.Val133=	synonymous_variant	1/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.399G>T	p.Val133=	synonymous_variant	1/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.399G>T	p.Val133=	synonymous_variant	1/15	1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61088 AN: 151720 Hom.: 12674 Cov.: 32

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

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.: 68 AF XY: 0.435 AC XY: 296994 AN XY: 682622

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.: 32 AF XY: 0.398 AC XY: 29568 AN XY: 74204

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

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	- -

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

Likely 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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	11
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

Other links and lift over

dbSNP: rs9462858; hg19: chr6-42946490; COSMIC: COSV55102374;