Genetic Variant PEX3:p.Trp6Arg (chr6-143451058-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003630.3(PEX3):c.16T>C(p.Trp6Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

PEX3
NM_003630.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.75

Variant links:

Genes affected

PEX3 (HGNC:8858): (peroxisomal biogenesis factor 3) The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. 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. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

PEX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41554072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX3	NM_003630.3 link	c.16T>C	p.Trp6Arg	missense_variant	Exon 1 of 12	ENST00000367591.5	NP_003621.1	P56589

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX3	ENST00000367591.5 link	c.16T>C	p.Trp6Arg	missense_variant	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4		P56589
PEX3	ENST00000367592.5 link	c.16T>C	p.Trp6Arg	missense_variant	Exon 1 of 7	5		ENSP00000356564.1		Q7Z6V3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 10B

Uncertain:1

Nov 05, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

0.058

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

.;L

PhyloP100

4.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.81

T;T

Sift4G

Pathogenic

0.0010

D;T

Polyphen

0.99

.;D

Vest4

0.83

MutPred

0.59

Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);

MVP

0.80

MPC

1.4

ClinPred

0.90

GERP RS

4.7

PromoterAI

0.13

Neutral

(source)

Varity_R

0.73

gMVP

0.33

Mutation Taster

=61/39

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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