rs536486149

Variant summary

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

The NM_002617.4(PEX10):​c.640C>T​(p.Arg214Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000764 in 1,609,572 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R214H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000078 ( 1 hom. )

Consequence

PEX10
NM_002617.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.705
Variant links:
Genes affected
PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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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
PEX10NM_002617.4 linkc.640C>T p.Arg214Cys missense_variant 4/6 ENST00000447513.7 NP_002608.1 O60683-1A0A024R068

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PEX10ENST00000447513.7 linkc.640C>T p.Arg214Cys missense_variant 4/61 NM_002617.4 ENSP00000407922.2 O60683-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152236
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000627
AC:
15
AN:
239380
Hom.:
0
AF XY:
0.000100
AC XY:
13
AN XY:
130042
show subpopulations
Gnomad AFR exome
AF:
0.0000672
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000204
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000742
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000782
AC:
114
AN:
1457218
Hom.:
1
Cov.:
35
AF XY:
0.0000801
AC XY:
58
AN XY:
724542
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000199
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000838
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152354
Hom.:
0
Cov.:
34
AF XY:
0.0000671
AC XY:
5
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000578
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2021The c.700C>T (p.R234C) alteration is located in exon 4 (coding exon 4) of the PEX10 gene. This alteration results from a C to T substitution at nucleotide position 700, causing the arginine (R) at amino acid position 234 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Peroxisome biogenesis disorder, complementation group 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2022This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the PEX10 protein (p.Arg234Cys). This variant is present in population databases (rs536486149, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PEX10-related conditions. ClinVar contains an entry for this variant (Variation ID: 446046). 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. -
Zellweger spectrum disorders Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 05, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.65
.;D;T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.75
T;T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.59
D;D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Pathogenic
3.6
.;H;.
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.022
D;D;D
Sift4G
Uncertain
0.0070
D;D;D
Polyphen
0.28
B;B;.
Vest4
0.41
MutPred
0.76
.;Loss of disorder (P = 0.0137);Loss of disorder (P = 0.0137);
MVP
0.78
MPC
0.16
ClinPred
0.21
T
GERP RS
4.0
Varity_R
0.13
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs536486149; hg19: chr1-2338295; COSMIC: COSV99992234; COSMIC: COSV99992234; API