rs12375

chr1-10536284-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004565.3(PEX14):c.156C>T(p.Phe52=) 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:6
• Conservation: PhyloP100: 1.38

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr1-10536284-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PEX14	NM_004565.3	c.156C>T	p.Phe52=	synonymous_variant	3/9	ENST00000356607.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX14	ENST00000356607.9	c.156C>T	p.Phe52=	synonymous_variant	3/9	1	NM_004565.3	P1
PEX14	ENST00000491661.2	c.141C>T	p.Phe47=	synonymous_variant	3/6	2
PEX14	ENST00000472851.1	n.517C>T		non_coding_transcript_exon_variant	4/4	3
PEX14	ENST00000492696.1	n.245C>T		non_coding_transcript_exon_variant	2/2	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

GnomAD3 exomes AF: 0.295 AC: 74030 AN: 251160 Hom.: 11751 AF XY: 0.291 AC XY: 39564 AN XY: 135784

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 SAS exome AF: 0.229

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

Gnomad4 AFR exome AF: 0.0987

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.297

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

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.275

Alfa AF: 0.298 Hom.: 5010

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -

Peroxisome biogenesis disorder 13A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Peroxisome biogenesis disorder, complementation group K Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	13
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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