rs12375

Variant names:

• chr1-10536284-C-T
• rs12375
• NM_004565.3:c.156C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004565.3(PEX14):​c.156C>T​(p.Phe52Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,596,574 control chromosomes in the GnomAD database, including 77,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5741 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71803 hom.)
• Consequence: PEX14 NM_004565.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.38
• Publications: 24 publications found

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]

PEX14 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 13A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-10536284-C-T is Benign according to our data. Variant chr1-10536284-C-T is described in ClinVar as [Benign]. Clinvar id is 259434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX14	NM_004565.3	c.156C>T	p.Phe52Phe	synonymous_variant	Exon 3 of 9	ENST00000356607.9	NP_004556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX14	ENST00000356607.9	c.156C>T	p.Phe52Phe	synonymous_variant	Exon 3 of 9	1	NM_004565.3	ENSP00000349016.4
PEX14	ENST00000491661.2	c.141C>T	p.Phe47Phe	synonymous_variant	Exon 3 of 6	2		ENSP00000465473.1
PEX14	ENST00000472851.1	n.517C>T		non_coding_transcript_exon_variant	Exon 4 of 4	3
PEX14	ENST00000492696.1	n.245C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39120 AN: 151842 Hom.: 5742 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.295 AC: 74030 AN: 251160 AF XY: 0.291

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.310 AC: 447902 AN: 1444612 Hom.: 71803 Cov.: 28 AF XY: 0.307 AC XY: 221248 AN XY: 719704

African (AFR) AF: 0.0987 AC: 3280 AN: 33244

American (AMR) AF: 0.403 AC: 18025 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6938 AN: 26020

East Asian (EAS) AF: 0.186 AC: 7391 AN: 39642

South Asian (SAS) AF: 0.223 AC: 19142 AN: 85992

European-Finnish (FIN) AF: 0.332 AC: 17737 AN: 53386

Middle Eastern (MID) AF: 0.228 AC: 1306 AN: 5740

European-Non Finnish (NFE) AF: 0.325 AC: 356349 AN: 1096072

Other (OTH) AF: 0.297 AC: 17734 AN: 59810

GnomAD4 genome AF: 0.257 AC: 39111 AN: 151962 Hom.: 5741 Cov.: 31 AF XY: 0.258 AC XY: 19127 AN XY: 74250

African (AFR) AF: 0.107 AC: 4448 AN: 41492

American (AMR) AF: 0.337 AC: 5154 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 920 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1073 AN: 5152

South Asian (SAS) AF: 0.239 AC: 1147 AN: 4808

European-Finnish (FIN) AF: 0.338 AC: 3561 AN: 10526

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21842 AN: 67926

Other (OTH) AF: 0.275 AC: 580 AN: 2110

Alfa AF: 0.297 Hom.: 7510

Bravo AF: 0.253

Asia WGS AF: 0.253 AC: 879 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.318

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 13A (Zellweger) Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder, complementation group K Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12375; hg19: chr1-10596341; COSMIC: COSV63060246;