rs1129187

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000287.4(PEX6):c.2816C>G(p.Pro939Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P939Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.306

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:

PEX6 (HGNC:):

PEX6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062992275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4 linkuse as main transcript	c.2816C>G	p.Pro939Arg	missense_variant	17/17	ENST00000304611.13	NP_000278.3	Q13608-1A0A024RD09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 linkuse as main transcript	c.2816C>G	p.Pro939Arg	missense_variant	17/17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546 linkuse as main transcript	c.*352C>G		3_prime_UTR_variant	15/15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248532

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461076

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2021

- -

Peroxisome biogenesis disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 939 of the PEX6 protein (p.Pro939Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PEX6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1035564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.5

DANN

Benign

0.97

DEOGEN2

Benign

0.079

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.20

Sift

Benign

0.082

Sift4G

Benign

0.49

Polyphen

0.040

Vest4

0.10

MutPred

0.19

Loss of glycosylation at P939 (P = 0.0409);

MVP

0.84

MPC

0.16

ClinPred

0.17

GERP RS

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.11

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

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