1-2406891-C-G

Variant names:

• chr1-2406891-C-G
• NM_002617.4:c.605G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002617.4(PEX10):​c.605G>C​(p.Arg202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R202H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.443

Genes affected

PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4	c.605G>C	p.Arg202Pro	missense_variant	Exon 4 of 6	ENST00000447513.7	NP_002608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.605G>C	p.Arg202Pro	missense_variant	Exon 4 of 6	1	NM_002617.4	ENSP00000407922.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder, complementation group 7 Uncertain:1

May 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2007338). This variant has not been reported in the literature in individuals affected with PEX10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 222 of the PEX10 protein (p.Arg222Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.40	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0080	D;T;T
Sift4G	Uncertain	0.041	D;T;T
Polyphen		0.15	B;D;.
Vest4		0.65
MutPred		0.71		.;Loss of methylation at R202 (P = 0.012);Loss of methylation at R202 (P = 0.012);
MVP		0.74
MPC		0.16
ClinPred		0.41	T
GERP RS		0.92
Varity_R		0.55
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-2338330;