NM_004565.3:c.959G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004565.3(PEX14):c.959G>A(p.Arg320Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,592,494 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 22 hom. )

Consequence

PEX14
NM_004565.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.35

Publications

5 publications found

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]

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

PEX14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027313828).

BP6

Variant 1-10629812-G-A is Benign according to our data. Variant chr1-10629812-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00847 (1289/152164) while in subpopulation AFR AF = 0.0296 (1230/41502). AF 95% confidence interval is 0.0283. There are 20 homozygotes in GnomAd4. There are 628 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

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.959G>A	p.Arg320Lys	missense	Exon 9 of 9	NP_004556.1	O75381-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX14	ENST00000356607.9	TSL:1 MANE Select	c.959G>A	p.Arg320Lys	missense	Exon 9 of 9	ENSP00000349016.4	O75381-1
PEX14	ENST00000889280.1		c.956G>A	p.Arg319Lys	missense	Exon 9 of 9	ENSP00000559339.1
PEX14	ENST00000923290.1		c.911G>A	p.Arg304Lys	missense	Exon 8 of 8	ENSP00000593349.1

Frequencies

GnomAD3 genomes

AF:

0.00846

AC:

1287

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00209

AC:

483

AN:

231224

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.000935

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000678

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000808

AC:

1164

AN:

1440330

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

492

AN XY:

716418

show subpopulations

African (AFR)

AF:

0.0301

AC:

998

AN:

33166

American (AMR)

AF:

0.000962

AC:

AN:

42640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39156

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52676

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1096426

Other (OTH)

AF:

0.00153

AC:

AN:

59598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00847

AC:

1289

AN:

152164

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

628

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0296

AC:

1230

AN:

41502

American (AMR)

AF:

0.00144

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67992

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.00974

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0310

AC:

136

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Peroxisome biogenesis disorder 13A (Zellweger) (1)

Peroxisome biogenesis disorder, complementation group K (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.27

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.44

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.24

REVEL

Benign

0.064

Sift

Benign

0.55

Sift4G

Benign

0.63

Polyphen

0.0020

Vest4

0.083

MVP

0.20

MPC

0.43

ClinPred

0.0014

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.038

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over