rs11539736

Positions:

• chr6-42978944-G-A
• chr6-42978944-G-C

Variant summary

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

The ENST00000304611.13(PEX6):​c.207C>T​(p.Pro69=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,494,790 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (95 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (92 hom.)
• Consequence: PEX6 ENST00000304611.13 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.67

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=-0.69).
• BP6: Variant 6-42978944-G-A is Benign according to our data. Variant chr6-42978944-G-A is described in ClinVar as [Benign]. Clinvar id is 92782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4	c.207C>T	p.Pro69=	synonymous_variant	1/17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.207C>T	p.Pro69=	synonymous_variant	1/17	1	NM_000287.4	ENSP00000303511	P1
PEX6	ENST00000244546.4	c.207C>T	p.Pro69=	synonymous_variant	1/15	1		ENSP00000244546

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3229 AN: 152060 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.00227 AC: 212 AN: 93208 Hom.: 6 AF XY: 0.00203 AC XY: 107 AN XY: 52710

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00237

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00195 AC: 2615 AN: 1342622 Hom.: 92 Cov.: 35 AF XY: 0.00173 AC XY: 1149 AN XY: 662296

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.0212 AC: 3231 AN: 152168 Hom.: 95 Cov.: 32 AF XY: 0.0204 AC XY: 1519 AN XY: 74400

Gnomad4 AFR AF: 0.0736

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.0242

Asia WGS AF: 0.00145 AC: 5 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 11, 2013

- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

- -

Peroxisome biogenesis disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.1
DANN	Benign	0.95

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: rs11539736; hg19: chr6-42946682;