6-42965078-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_000287.4(PEX6):c.2663G>A(p.Arg888His) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R888L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PEX6 NM_000287.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 4.64

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42965078-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520796.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 6-42965078-C-T is Pathogenic according to our data. Variant chr6-42965078-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1683990.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.2663G>A	p.Arg888His	missense_variant	15/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.2663G>A	p.Arg888His	missense_variant	15/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.*199G>A		3_prime_UTR_variant	13/15	1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461762 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74364

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 4A (Zellweger) Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Wangler Lab, Baylor College of Medicine	Feb 10, 2023	This missense change (c.2663G>A ,p.R888H) in PEX6 was seen in trans with c.1220C>A (p.T407N) (PM3). This variant is reported in an moderately to severely affected patient by Wangler et al. (PMID: 29419819). An alternate amino acid change at the same location is reported to be pathogenic (p.R888P) and this change is not seen in population databases of healthy individuals (PM2). We interpret this variant to be likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 21, 2023	This PEX6 missense variant has been reported to occur in the compound heterozygous state in two siblings affected with Zellweger spectrum disorder6. This variant (rs267608247) is rare (<0.1%) in a large population dataset7 (gnomAD v2.1.1: 2/31402 total alleles; 0.0064%; no homozygotes) and has been reported in ClinVar (Variation ID 1683990). Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. While the arginine residue at this position is evolutionarily conserved across many of the species assessed, histidine is present in a few species. We consider c.2663G>A;p.Arg888His in PEX6 to be likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 19877282) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 28, 2023

Variant summary: PEX6 c.2663G>A (p.Arg888His) results in a non-conservative amino acid change in the encoded protein sequence. Another missense variant altering this residue (p.Arg888Pro) has been classified as likely pathogenic by a ClinVar submitter. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2663G>A has been reported in the literature in an individual affected with Zellweger Syndrome who was compound heterozygous with a variant that may be pathogenic (Wangler_2018). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29419819). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Peroxisome biogenesis disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 28, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 888 of the PEX6 protein (p.Arg888His). This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PEX6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	0.085
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.73
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.44	B
Vest4		0.29
MutPred		0.66		Loss of MoRF binding (P = 0.0191);
MVP		0.88
MPC		0.24
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608247; hg19: chr6-42932816;