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: Ambry Genetics, G2P, 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004565.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	NM_004565.3	MANE Select	c.156C>T	p.Phe52Phe	synonymous	Exon 3 of 9	NP_004556.1	O75381-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	ENST00000356607.9	TSL:1 MANE Select	c.156C>T	p.Phe52Phe	synonymous	Exon 3 of 9	ENSP00000349016.4	O75381-1
	PEX14	ENST00000889280.1		c.156C>T	p.Phe52Phe	synonymous	Exon 3 of 9	ENSP00000559339.1
	PEX14	ENST00000923290.1		c.108C>T	p.Phe36Phe	synonymous	Exon 2 of 8	ENSP00000593349.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Peroxisome biogenesis disorder 13A (Zellweger) (2)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder, complementation group K (1)

Computational scores

Source: dbNSFP v4.9

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;