rs144256391

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002857.4(PEX19):c.115C>T(p.Pro39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

PEX19
NM_002857.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:1

Conservation

PhyloP100: 2.74

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034288466).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000309 (47/152292) while in subpopulation AMR AF= 0.000523 (8/15306). AF 95% confidence interval is 0.000292. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEX19	NM_002857.4 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	2/8	ENST00000368072.10	NP_002848.1
PEX19	NM_001193644.1 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	2/8		NP_001180573.1
PEX19	NR_036493.2 linkuse as main transcript	n.124C>T		non_coding_transcript_exon_variant	2/7
PEX19	NR_036492.2 linkuse as main transcript	n.80-486C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX19	ENST00000368072.10 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	2/8	1	NM_002857.4	ENSP00000357051	P1	P40855-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000338

AC:

AN:

251460

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000231

AC:

337

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000309

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000370

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 12A (Zellweger)

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 39 of the PEX19 protein (p.Pro39Ser). This variant is present in population databases (rs144256391, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with PEX19-related conditions. ClinVar contains an entry for this variant (Variation ID: 499937). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PEX19 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.115C>T (p.P39S) alteration is located in exon 2 (coding exon 2) of the PEX19 gene. This alteration results from a C to T substitution at nucleotide position 115, causing the proline (P) at amino acid position 39 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PEX19-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D;N

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.15

Sift

Benign

0.43

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;.

Vest4

0.31

MVP

0.29

MPC

0.053

ClinPred

0.0076

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over