chr1-10474984-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004565.3(PEX14):ā€‹c.18G>Cā€‹(p.Gln6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,609,784 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 Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q6E) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00018 ( 0 hom., cov: 33)
Exomes š‘“: 0.00020 ( 0 hom. )

Consequence

PEX14
NM_004565.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24256217).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PEX14NM_004565.3 linkuse as main transcriptc.18G>C p.Gln6His missense_variant 1/9 ENST00000356607.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PEX14ENST00000356607.9 linkuse as main transcriptc.18G>C p.Gln6His missense_variant 1/91 NM_004565.3 P1O75381-1
PEX14ENST00000491661.2 linkuse as main transcriptc.3G>C p.Gln1His missense_variant 1/62
PEX14ENST00000472851.1 linkuse as main transcriptn.293+2404G>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.000323
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000134
AC:
32
AN:
239506
Hom.:
0
AF XY:
0.000115
AC XY:
15
AN XY:
130334
show subpopulations
Gnomad AFR exome
AF:
0.000135
Gnomad AMR exome
AF:
0.0000888
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:
0.000251
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000201
AC:
293
AN:
1457556
Hom.:
0
Cov.:
31
AF XY:
0.000199
AC XY:
144
AN XY:
724632
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000158
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000244
Gnomad4 OTH exome
AF:
0.000200
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000323
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000237
Hom.:
0
Bravo
AF:
0.000144
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000350
AC:
3
ExAC
AF:
0.000157
AC:
19

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2023The c.18G>C (p.Q6H) alteration is located in exon 1 (coding exon 1) of the PEX14 gene. This alteration results from a G to C substitution at nucleotide position 18, causing the glutamine (Q) at amino acid position 6 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Peroxisome biogenesis disorder, complementation group K Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 04, 2022This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 6 of the PEX14 protein (p.Gln6His). This variant is present in population databases (rs200395336, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PEX14-related conditions. ClinVar contains an entry for this variant (Variation ID: 500767). 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: "Tolerated"; PolyPhen-2: "Not Available"; 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 08, 2017- -
Peroxisome biogenesis disorder 13A (Zellweger) Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 23, 2022- -
PEX14-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 14, 2024The PEX14 c.18G>C variant is predicted to result in the amino acid substitution p.Gln6His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.35
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T;T
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.70
T;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.2
N;.
REVEL
Benign
0.089
Sift
Uncertain
0.012
D;.
Sift4G
Benign
0.092
T;D
Polyphen
0.84
P;.
Vest4
0.34
MutPred
0.080
Gain of loop (P = 0.0312);.;
MVP
0.51
MPC
0.40
ClinPred
0.13
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.57

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: rs200395336; hg19: chr1-10535041; API