6-143451062-A-G

Variant names:

• chr6-143451062-A-G
• NM_003630.3:c.20A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003630.3(PEX3):​c.20A>G​(p.Asn7Ser) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX3 NM_003630.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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]

ACMG classification

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=0.32754505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX3	NM_003630.3	c.20A>G	p.Asn7Ser	missense_variant	Exon 1 of 12	ENST00000367591.5	NP_003621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX3	ENST00000367591.5	c.20A>G	p.Asn7Ser	missense_variant	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4
PEX3	ENST00000367592.5	c.20A>G	p.Asn7Ser	missense_variant	Exon 1 of 7	5		ENSP00000356564.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 7 of the PEX3 protein (p.Asn7Ser). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PEX3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.76	T;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PhyloP100		4.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.099
Sift	Benign	0.062	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.016	.;B
Vest4		0.20
MutPred		0.43		Gain of disorder (P = 0.0305);Gain of disorder (P = 0.0305);
MVP		0.64
MPC		0.30
ClinPred		0.77	D
GERP RS		3.5
PromoterAI		-0.063	Neutral
Varity_R		0.16
gMVP		0.60
Mutation Taster		=84/16	polymorphism

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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Other links and lift over

hg19: chr6-143772199;