Genetic Variant PEX10:p.Met1? (chr1-2412501-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_002617.4(PEX10):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000826 in 1,210,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

PEX10
NM_002617.4 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.10

Publications

0 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 145 codons. Genomic position: 2408619. Lost 0.441 part of the original CDS.

PS1

Another start lost variant in NM_002617.4 (PEX10) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 6	ENST00000447513.7	NP_002608.1	O60683-1A0A024R068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 6	1	NM_002617.4	ENSP00000407922.2		O60683-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.26e-7

AC:

AN:

1210336

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

590978

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24164

American (AMR)

AF:

0.00

AC:

AN:

13718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18018

East Asian (EAS)

AF:

0.00

AC:

AN:

26708

South Asian (SAS)

AF:

0.00

AC:

AN:

53466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29440

Middle Eastern (MID)

AF:

0.000292

AC:

AN:

3422

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

992054

Other (OTH)

AF:

0.00

AC:

AN:

49346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

.;T;T

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.029

PhyloP100

3.1

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;B;.

Vest4

0.61

MutPred

0.59

Gain of ubiquitination at M1 (P = 0.0128);Gain of ubiquitination at M1 (P = 0.0128);Gain of ubiquitination at M1 (P = 0.0128);

MVP

0.81

ClinPred

1.0

GERP RS

3.4

PromoterAI

-0.37

Neutral

(source)

Varity_R

0.98

gMVP

0.70

Mutation Taster

=3/197

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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