chr1-10474995-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004565.3(PEX14):ā€‹c.29C>Gā€‹(p.Pro10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,610,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P10S) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00074 ( 0 hom., cov: 33)
Exomes š‘“: 0.000070 ( 0 hom. )

Consequence

PEX14
NM_004565.3 missense

Scores

6
13

Clinical Significance

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

Conservation

PhyloP100: 2.98
Variant links:
Genes affected
PEX14 (HGNC:8856): (peroxisomal biogenesis factor 14) This gene encodes an essential component of the peroxisomal import machinery. The protein is integrated into peroxisome membranes with its C-terminus exposed to the cytosol, and interacts with the cytosolic receptor for proteins containing a PTS1 peroxisomal targeting signal. The protein also functions as a transcriptional corepressor and interacts with a histone deacetylase. A mutation in this gene results in one form of Zellweger syndrome. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0072695613).
BP6
Variant 1-10474995-C-G is Benign according to our data. Variant chr1-10474995-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 593805.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PEX14NM_004565.3 linkuse as main transcriptc.29C>G p.Pro10Arg missense_variant 1/9 ENST00000356607.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PEX14ENST00000356607.9 linkuse as main transcriptc.29C>G p.Pro10Arg missense_variant 1/91 NM_004565.3 P1O75381-1
PEX14ENST00000491661.2 linkuse as main transcriptc.14C>G p.Pro5Arg missense_variant 1/62
PEX14ENST00000472851.1 linkuse as main transcriptn.293+2415C>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000742
AC:
113
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00273
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000167
AC:
40
AN:
239350
Hom.:
0
AF XY:
0.000108
AC XY:
14
AN XY:
130148
show subpopulations
Gnomad AFR exome
AF:
0.00256
Gnomad AMR exome
AF:
0.0000297
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:
0.00000928
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000700
AC:
102
AN:
1457834
Hom.:
0
Cov.:
30
AF XY:
0.0000648
AC XY:
47
AN XY:
724824
show subpopulations
Gnomad4 AFR exome
AF:
0.00266
Gnomad4 AMR exome
AF:
0.0000905
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:
0.0000997
GnomAD4 genome
AF:
0.000742
AC:
113
AN:
152332
Hom.:
0
Cov.:
33
AF XY:
0.000671
AC XY:
50
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00272
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000793
Hom.:
0
Bravo
AF:
0.000771
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000165
AC:
20
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 24, 2017- -
Peroxisome biogenesis disorder, complementation group K Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2024- -
PEX14-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 31, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.0073
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.5
N;.
REVEL
Benign
0.055
Sift
Uncertain
0.014
D;.
Sift4G
Uncertain
0.026
D;T
Polyphen
0.87
P;.
Vest4
0.38
MVP
0.20
MPC
0.45
ClinPred
0.082
T
GERP RS
4.8
Varity_R
0.32
gMVP
0.37

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: rs12068754; hg19: chr1-10535052; API