rs757852291

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000318471.5(PEX7):​c.86C>T​(p.Pro29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,488,770 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P29A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PEX7
ENST00000318471.5 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.40
Variant links:
Genes affected
PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PEX7NM_000288.4 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant 1/10 ENST00000318471.5 NP_000279.1
PEX7XM_006715502.3 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant 1/7 XP_006715565.1
PEX7XM_047418874.1 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant 1/6 XP_047274830.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PEX7ENST00000318471.5 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant 1/101 NM_000288.4 ENSP00000315680 P1O00628-1
PEX7ENST00000367756.8 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant 1/43 ENSP00000356730
PEX7ENST00000541292.6 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant, NMD_transcript_variant 1/115 ENSP00000441004 O00628-2
PEX7ENST00000678593.1 linkuse as main transcriptc.86C>T p.Pro29Leu missense_variant, NMD_transcript_variant 1/8 ENSP00000503841

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151960
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0000725
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:
0.00318
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000337
AC:
3
AN:
89132
Hom.:
0
AF XY:
0.0000593
AC XY:
3
AN XY:
50574
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:
0.0000566
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000605
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000292
AC:
39
AN:
1336702
Hom.:
0
Cov.:
33
AF XY:
0.0000303
AC XY:
20
AN XY:
659500
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:
0.0000401
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000321
Gnomad4 OTH exome
AF:
0.0000361
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152068
Hom.:
0
Cov.:
35
AF XY:
0.0000403
AC XY:
3
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000281
AC:
1
Asia WGS
AF:
0.000290
AC:
1
AN:
3462

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 01, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 24, 2016- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 26, 2021The c.86C>T (p.P29L) alteration is located in exon 1 (coding exon 1) of the PEX7 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the proline (P) at amino acid position 29 to be replaced by a leucine (L). The in silico prediction for the p.P29L alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Peroxisome biogenesis disorder 9B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 15, 2022This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 29 of the PEX7 protein (p.Pro29Leu). This variant is present in population databases (rs757852291, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PEX7-related conditions. ClinVar contains an entry for this variant (Variation ID: 498141). 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: "Possibly 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. -
Rhizomelic chondrodysplasia punctata Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;T;D
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.82
T;T;T
M_CAP
Pathogenic
0.90
D
MetaRNN
Uncertain
0.52
D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Uncertain
2.6
M;.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.012
D;D;D
Sift4G
Uncertain
0.022
D;D;T
Polyphen
1.0
.;.;D
Vest4
0.22
MutPred
0.45
Loss of glycosylation at P29 (P = 0.07);Loss of glycosylation at P29 (P = 0.07);Loss of glycosylation at P29 (P = 0.07);
MVP
1.0
MPC
0.37
ClinPred
0.93
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.51
gMVP
0.67

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.

Other links and lift over

dbSNP: rs757852291; hg19: chr6-137143889; API