rs61752139

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_000287.4(PEX6):​c.35T>C​(p.Phe12Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000775 in 1,419,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F12F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000077 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PEX6
NM_000287.4 missense

Scores

6
7
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.95

Publications

1 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-42979116-A-G is Pathogenic according to our data. Variant chr6-42979116-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557609.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PEX6NM_000287.4 linkc.35T>C p.Phe12Ser missense_variant Exon 1 of 17 ENST00000304611.13 NP_000278.3 Q13608-1A0A024RD09

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PEX6ENST00000304611.13 linkc.35T>C p.Phe12Ser missense_variant Exon 1 of 17 1 NM_000287.4 ENSP00000303511.8 Q13608-1
PEX6ENST00000244546.4 linkc.35T>C p.Phe12Ser missense_variant Exon 1 of 15 1 ENSP00000244546.4 Q13608-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
185122
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000775
AC:
11
AN:
1419642
Hom.:
0
Cov.:
35
AF XY:
0.00000568
AC XY:
4
AN XY:
704162
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32820
American (AMR)
AF:
0.00
AC:
0
AN:
40980
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25628
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38250
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82386
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36512
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4254
European-Non Finnish (NFE)
AF:
0.00000909
AC:
10
AN:
1099678
Other (OTH)
AF:
0.0000169
AC:
1
AN:
59134
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74342
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41448
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Heimler syndrome 2 Pathogenic:1
Mar 19, 2024
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Uncertain:1
Apr 03, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Peroxisome biogenesis disorder Uncertain:1
Feb 21, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the PEX6 protein (p.Phe12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Zellweger spectrum disorder (PMID: 15542397). ClinVar contains an entry for this variant (Variation ID: 557609). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.054
T;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.70
T;T
M_CAP
Pathogenic
0.45
D
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Uncertain
0.29
D
MutationAssessor
Benign
1.9
L;L
PhyloP100
4.0
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.030
D;D
Polyphen
0.90
P;.
Vest4
0.43
MutPred
0.65
Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);
MVP
0.95
MPC
4.9
ClinPred
0.99
D
GERP RS
5.0
PromoterAI
-0.023
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.49
gMVP
0.72
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

dbSNP: rs61752139; hg19: chr6-42946854; API