dbSNP rs724160001: PEX10:p.Arg311Leu (chr1-2405815-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_002617.4(PEX10):c.932G>T(p.Arg311Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R311Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEX10
NM_002617.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.78

Publications

8 publications found

Variant links:

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]

PEX10 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 6A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health
peroxisome biogenesis disorder 6B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive ataxia due to PEX10 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a zinc_finger_region RING-type (size 38) in uniprot entity PEX10_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_002617.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-2405815-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162433.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4 link	c.932G>T	p.Arg311Leu	missense_variant	Exon 6 of 6	ENST00000447513.7	NP_002608.1	O60683-1A0A024R068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PEX10	ENST00000447513.7 link	c.932G>T	p.Arg311Leu	missense_variant	Exon 6 of 6	1	NM_002617.4	ENSP00000407922.2	O60683-1
PEX10	ENST00000288774.8 link	c.992G>T	p.Arg331Leu	missense_variant	Exon 6 of 6	1		ENSP00000288774.3	O60683-2
PEX10	ENST00000507596.5 link	c.926G>T	p.Arg309Leu	missense_variant	Exon 6 of 6	5		ENSP00000424291.1	D6RBB0
PEX10	ENST00000650293.1 link	n.884G>T		non_coding_transcript_exon_variant	Exon 6 of 8			ENSP00000497980.1	A0A3B3ITN6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718522

African (AFR)

AF:

0.00

AC:

AN:

33150

American (AMR)

AF:

0.00

AC:

AN:

43128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25872

East Asian (EAS)

AF:

0.00

AC:

AN:

38852

South Asian (SAS)

AF:

0.00

AC:

AN:

83644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105594

Other (OTH)

AF:

0.00

AC:

AN:

59780

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000249

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.2

.;M;.

PhyloP100

6.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.3

D;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.89

MutPred

0.65

.;Gain of catalytic residue at R311 (P = 0.0229);.;

MVP

0.85

MPC

0.55

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.77

Mutation Taster

=7/93

disease causing

(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

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over