chr1-10475010-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004565.3(PEX14):c.36+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,608,126 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 6 hom. )

Consequence

PEX14
NM_004565.3 splice_region, intron

Scores

Splicing: ADA: 0.07612

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.86

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 1-10475010-G-A is Benign according to our data. Variant chr1-10475010-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259436.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00109 (166/152350) while in subpopulation AMR AF = 0.00209 (32/15308). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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.36+8G>A		splice_region intron	N/A	NP_004556.1	O75381-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PEX14	ENST00000356607.9	TSL:1 MANE Select	c.36+8G>A	splice_region intron	N/A	ENSP00000349016.4	O75381-1
PEX14	ENST00000889280.1		c.36+8G>A	splice_region intron	N/A	ENSP00000559339.1
PEX14	ENST00000923290.1		c.36+8G>A	splice_region intron	N/A	ENSP00000593349.1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00151

AC:

356

AN:

236358

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.0000688

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000875

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00108

AC:

1571

AN:

1455776

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

794

AN XY:

723656

show subpopulations

African (AFR)

AF:

0.000808

AC:

AN:

33410

American (AMR)

AF:

0.00114

AC:

AN:

43986

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

557

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.000400

AC:

AN:

85014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52744

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5742

European-Non Finnish (NFE)

AF:

0.000564

AC:

626

AN:

1109288

Other (OTH)

AF:

0.00289

AC:

174

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

160

239

319

399

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:

0.00109

AC:

166

AN:

152350

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41594

American (AMR)

AF:

0.00209

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00250

Hom.:

Bravo

AF:

0.00123

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Peroxisome biogenesis disorder 13A (Zellweger) (1)

Peroxisome biogenesis disorder, complementation group K (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.97

PhyloP100

2.9

PromoterAI

0.085

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.076

dbscSNV1_RF

Benign

0.15

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