rs9462858

Variant names:

• chr6-42978752-C-A
• rs9462858
• NM_000287.4:c.399G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-42978752-C-A
• chr6-42978752-C-G
• chr6-42978752-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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 (★★). 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:12
• Conservation: PhyloP100: 0.405
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.399G>T	p.Val133Val	synonymous_variant	Exon 1 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.399G>T	p.Val133Val	synonymous_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.399G>T	p.Val133Val	synonymous_variant	Exon 1 of 15	1		ENSP00000244546.4

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

GnomAD2 exomes AF: 0.377 AC: 49572 AN: 131414 AF XY: 0.388

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 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

African (AFR) AF: 0.378 AC: 11950 AN: 31590

American (AMR) AF: 0.283 AC: 10094 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10390 AN: 25116

East Asian (EAS) AF: 0.127 AC: 4535 AN: 35796

South Asian (SAS) AF: 0.434 AC: 34435 AN: 79276

European-Finnish (FIN) AF: 0.389 AC: 13277 AN: 34158

Middle Eastern (MID) AF: 0.471 AC: 2369 AN: 5030

European-Non Finnish (NFE) AF: 0.453 AC: 489116 AN: 1078746

Other (OTH) AF: 0.416 AC: 24064 AN: 57788

GnomAD4 genome AF: 0.403 AC: 61125 AN: 151838 Hom.: 12678 Cov.: 32 AF XY: 0.398 AC XY: 29568 AN XY: 74204

African (AFR) AF: 0.374 AC: 15473 AN: 41424

American (AMR) AF: 0.339 AC: 5182 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3470

East Asian (EAS) AF: 0.103 AC: 530 AN: 5140

South Asian (SAS) AF: 0.405 AC: 1947 AN: 4810

European-Finnish (FIN) AF: 0.406 AC: 4285 AN: 10560

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.454 AC: 30767 AN: 67842

Other (OTH) AF: 0.413 AC: 873 AN: 2112

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

Submissions by phenotype

not provided Benign:4

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.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. -

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Jul 10, 2018

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: Likely 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	-0.64
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		0.41
PromoterAI		0.14	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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