rs144256391

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39A) has been classified 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

1
17

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]

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 rank MANE Protein UniProt
PEX19NM_002857.4 linkc.115C>T p.Pro39Ser missense_variant Exon 2 of 8 ENST00000368072.10 NP_002848.1 P40855-1A0A0S2Z497
PEX19NM_001193644.1 linkc.115C>T p.Pro39Ser missense_variant Exon 2 of 8 NP_001180573.1 P40855
PEX19NR_036493.2 linkn.124C>T non_coding_transcript_exon_variant Exon 2 of 7
PEX19NR_036492.2 linkn.80-486C>T intron_variant Intron 1 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PEX19ENST00000368072.10 linkc.115C>T p.Pro39Ser missense_variant Exon 2 of 8 1 NM_002857.4 ENSP00000357051.5 P40855-1

Frequencies

GnomAD3 genomes
AF:
0.000309
AC:
47
AN:
152174
Hom.:
0
Cov.:
32
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:
85
AN:
251460
Hom.:
0
AF XY:
0.000338
AC XY:
46
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.:
2
Cov.:
31
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:
47
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.000309
AC XY:
23
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.:
0
Bravo
AF:
0.000332
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000264
AC:
32
Asia WGS
AF:
0.000577
AC:
2
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
Nov 22, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:2
Dec 07, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Apr 13, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 19, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
17
DANN
Benign
0.93
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.33
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.69
T;T
M_CAP
Benign
0.0016
T
MetaRNN
Benign
0.034
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;.
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
T
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.

Other links and lift over

dbSNP: rs144256391; hg19: chr1-160253385; COSMIC: COSV63619526; COSMIC: COSV63619526; API