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 testingInvitaeOct 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, criteria provided, single submitterclinical 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