dbSNP rs146644725: PEX19:p.Phe87Phe (chr1-160283029-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_002857.4(PEX19):c.261C>T(p.Phe87Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,614,122 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 7 hom. )

Consequence

PEX19
NM_002857.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.441

Publications

5 publications found

Variant links:

Genes affected

PEX19 (HGNC:9713): (peroxisomal biogenesis factor 19) This gene is necessary for early peroxisomal biogenesis. It acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. These disorders have at least 14 complementation groups, with more than one phenotype being observed for some complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of Zellweger syndrome (ZWS), as well as peroxisome biogenesis disorder complementation group 14 (PBD-CG14), which is also known as PBD-CGJ. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

PEX19 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 12A (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

PEX19 links:

ENSG00000258465 (HGNC:):

ENSG00000258465 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 1-160283029-G-A is Benign according to our data. Variant chr1-160283029-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284050.

BP7

Synonymous conserved (PhyloP=-0.441 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00204 (311/152260) while in subpopulation NFE AF = 0.00335 (228/68018). AF 95% confidence interval is 0.003. There are 1 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002857.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX19	NM_002857.4	MANE Select	c.261C>T	p.Phe87Phe	synonymous	Exon 3 of 8	NP_002848.1	A0A0S2Z497
PEX19	NM_001193644.1		c.261C>T	p.Phe87Phe	synonymous	Exon 3 of 8	NP_001180573.1	P40855
PEX19	NR_036492.2		n.160C>T		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX19	ENST00000368072.10	TSL:1 MANE Select	c.261C>T	p.Phe87Phe	synonymous	Exon 3 of 8	ENSP00000357051.5	P40855-1
PEX19	ENST00000472750.5	TSL:1	n.*28C>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434633.1	P40855-6
PEX19	ENST00000472750.5	TSL:1	n.*28C>T		3_prime_UTR	Exon 2 of 7	ENSP00000434633.1	P40855-6

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00185

AC:

464

AN:

251482

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00323

AC:

4728

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

2322

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33478

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00152

AC:

131

AN:

86246

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00395

AC:

4389

AN:

1112002

Other (OTH)

AF:

0.00233

AC:

141

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

274

549

823

1098

1372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00204

AC:

311

AN:

152260

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41542

American (AMR)

AF:

0.00177

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00335

AC:

228

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

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:

0.00219

Hom.:

Bravo

AF:

0.00221

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00373

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Peroxisome biogenesis disorder 12A (Zellweger) (2)

not specified (1)

PEX19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.4

(source)

DANN

Benign

0.74

PhyloP100

-0.44

Mutation Taster

=276/24

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