rs61736380

Positions:

• chr1-2406784-C-G
• chr1-2406784-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002617.4(PEX10):​c.712G>C​(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,610,650 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G238S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.469

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010670394).
• BP6: Variant 1-2406784-C-G is Benign according to our data. Variant chr1-2406784-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr1-2406784-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152332) while in subpopulation NFE AF= 0.00209 (142/68030). AF 95% confidence interval is 0.00181. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX10	NM_002617.4	c.712G>C	p.Gly238Arg	missense_variant	4/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.712G>C	p.Gly238Arg	missense_variant	4/6	1	NM_002617.4	P4

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152214 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00129 AC: 312 AN: 241814 Hom.: 0 AF XY: 0.00136 AC XY: 179 AN XY: 131790

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.000401

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00113 AC: 1643 AN: 1458318 Hom.: 3 Cov.: 35 AF XY: 0.00116 AC XY: 844 AN XY: 725264

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000513

Gnomad4 FIN exome AF: 0.000326

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152332 Hom.: 1 Cov.: 34 AF XY: 0.00158 AC XY: 118 AN XY: 74484

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00136

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00116 AC: 141

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger) Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 18, 2018

- -

PEX10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Zellweger spectrum disorders Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Peroxisome biogenesis disorder, complementation group 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.82	P;P;.
Vest4		0.31
MVP		0.84
MPC		0.22
ClinPred		0.038	T
GERP RS		-0.23
Varity_R		0.058
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736380; hg19: chr1-2338223;