rs201884779

Positions:

• chr22-18078576-A-G

Variant summary

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

The NM_001127649.3(PEX26):​c.200A>G​(p.Asn67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,599,366 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: -0.923

Genes affected

PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

ENSG00000288683 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043507814).
• BP6: Variant 22-18078576-A-G is Benign according to our data. Variant chr22-18078576-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288461.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr22-18078576-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (267/152190) while in subpopulation NFE AF= 0.00315 (214/67980). AF 95% confidence interval is 0.0028. There are 1 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.200A>G	p.Asn67Ser	missense_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.200A>G	p.Asn67Ser	missense_variant	2/6		NP_060399.1
PEX26	NM_001199319.2	c.200A>G	p.Asn67Ser	missense_variant	2/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.200A>G	p.Asn67Ser	missense_variant	1/5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.200A>G		non_coding_transcript_exon_variant	2/9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152072 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00136 AC: 294 AN: 216380 Hom.: 0 AF XY: 0.00144 AC XY: 173 AN XY: 119874

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000742

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.000729

GnomAD4 exome AF: 0.00277 AC: 4002 AN: 1447176 Hom.: 7 Cov.: 31 AF XY: 0.00271 AC XY: 1952 AN XY: 719300

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000912

Gnomad4 FIN exome AF: 0.000333

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152190 Hom.: 1 Cov.: 32 AF XY: 0.00151 AC XY: 112 AN XY: 74406

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00180

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00159 AC: 13

ExAC AF: 0.000991 AC: 118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2017	The N67S variant in the PEX26 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 75/25,018 alleles (0.3%) from individuals of non-Finnish European background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). The N67S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. As there is not enough information currently available to determine if this variant is pathogenic or benign, we interpret N67S as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PEX26: BP4 -

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Peroxisome biogenesis disorder 7A (Zellweger) Uncertain:1

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. -

PEX26-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.33
DANN	Benign	0.59
DEOGEN2	Benign	0.12	.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.65	T;.;T;.
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	-0.67	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.14	.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.70	.;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.065
MVP		0.51
MPC		0.13
ClinPred		0.0031	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.094

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: rs201884779; hg19: chr22-18561342;