rs34154371

chr1-2406576-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002617.4(PEX10):c.820A>G(p.Thr274Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,202 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T274I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 33)
  • Exomes 𝑓: 0.023 (465 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.96

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002617.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0106090605).
• BP6: Variant 1-2406576-T-C is Benign according to our data. Variant chr1-2406576-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 197887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2406576-T-C is described in Lovd as [Benign]. Variant chr1-2406576-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2850/152162) while in subpopulation NFE AF= 0.0264 (1793/67986). AF 95% confidence interval is 0.0254. There are 42 homozygotes in gnomad4. There are 1323 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX10	NM_002617.4	c.820A>G	p.Thr274Ala	missense_variant	5/6	ENST00000447513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.820A>G	p.Thr274Ala	missense_variant	5/6	1	NM_002617.4	P4

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2851 AN: 152044 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00975

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0203 AC: 5069 AN: 250264 Hom.: 85 AF XY: 0.0205 AC XY: 2781 AN XY: 135646

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00944

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0286

GnomAD4 exome AF: 0.0231 AC: 33805 AN: 1461040 Hom.: 465 Cov.: 34 AF XY: 0.0230 AC XY: 16719 AN XY: 726848

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0824

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0248

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0187 AC: 2850 AN: 152162 Hom.: 42 Cov.: 33 AF XY: 0.0178 AC XY: 1323 AN XY: 74384

Gnomad4 AFR AF: 0.00472

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0842

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00976

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0270 Hom.: 62

Bravo AF: 0.0182

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0188 AC: 2277

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0310

EpiControl AF: 0.0271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13006=2% -

Peroxisome biogenesis disorder 6A (Zellweger) Benign:2

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Thr294Ala variant in PEX10 has been identified in cis with a frameshift mutation and in an individual with Zellweger syndrome (PMID: 19127411). This variant has been identified in >2% of European (non-Finnish) chromosomes and 36 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Zellweger syndrome. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	This variant is associated with the following publications: (PMID: 15542397, 27535533, 19127411) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Peroxisome biogenesis disorder, complementation group 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Zellweger spectrum disorders Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.95	P;D;.
Vest4		0.47
MPC		0.19
ClinPred		0.020	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs34154371; hg19: chr1-2338015; COSMIC: COSV56580904; COSMIC: COSV56580904;