rs17851387

chr22-18088068-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001127649.3(PEX26):c.911G>A(p.Arg304His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,602,860 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R304C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.154

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067124367).
• BP6: Variant 22-18088068-G-A is Benign according to our data. Variant chr22-18088068-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287097.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr22-18088068-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (172/152262) while in subpopulation NFE AF= 0.00146 (99/68016). AF 95% confidence interval is 0.00122. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX26	NM_001127649.3	c.911G>A	p.Arg304His	missense_variant	5/5	ENST00000399744.8
PEX26	NM_017929.6	c.911G>A	p.Arg304His	missense_variant	6/6
PEX26	NM_001199319.2	c.764G>A	p.Arg255His	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.911G>A	p.Arg304His	missense_variant	5/5	1	NM_001127649.3	P1
PEX26	ENST00000329627.11	c.911G>A	p.Arg304His	missense_variant	6/6	1		P1
PEX26	ENST00000428061.2	c.764G>A	p.Arg255His	missense_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00107 AC: 268 AN: 250416 Hom.: 0 AF XY: 0.00113 AC XY: 153 AN XY: 135440

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000867

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00134 AC: 1937 AN: 1450598 Hom.: 3 Cov.: 29 AF XY: 0.00131 AC XY: 947 AN XY: 722442

Gnomad4 AFR exome AF: 0.000871

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00564

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000979

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74470

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00119 AC: 145

EpiCase AF: 0.00109

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 09, 2017

- -

PEX26-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2019

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	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	2.9
Dann	Benign	0.96
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.65	T;.;T;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.19	T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.0060	.;B;B;.
Vest4		0.070
MVP		0.81
MPC		0.21
ClinPred		0.0063	T
GERP RS		-5.7
Varity_R		0.024
gMVP		0.22

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: rs17851387; hg19: chr22-18570834;