rs12484657

Positions:

• chr22-18083522-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127649.3(PEX26):​c.457C>G​(p.Leu153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,614,136 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.016 (211 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009204537).
• BP6: Variant 22-18083522-C-G is Benign according to our data. Variant chr22-18083522-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 95877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18083522-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1610/152348) while in subpopulation NFE AF= 0.0174 (1181/68030). AF 95% confidence interval is 0.0165. There are 21 homozygotes in gnomad4. There are 726 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX26	NM_001127649.3	c.457C>G	p.Leu153Val	missense_variant	3/5	ENST00000399744.8
PEX26	NM_017929.6	c.457C>G	p.Leu153Val	missense_variant	4/6
PEX26	NM_001199319.2	c.457C>G	p.Leu153Val	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.457C>G	p.Leu153Val	missense_variant	3/5	1	NM_001127649.3	P1
PEX26	ENST00000329627.11	c.457C>G	p.Leu153Val	missense_variant	4/6	1		P1
PEX26	ENST00000428061.2	c.457C>G	p.Leu153Val	missense_variant	3/4	1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1611 AN: 152230 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0102 AC: 2557 AN: 251270 Hom.: 24 AF XY: 0.0104 AC XY: 1410 AN XY: 135790

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0157 AC: 22897 AN: 1461788 Hom.: 211 Cov.: 32 AF XY: 0.0153 AC XY: 11152 AN XY: 727182

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0106 AC: 1610 AN: 152348 Hom.: 21 Cov.: 33 AF XY: 0.00974 AC XY: 726 AN XY: 74506

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0160 Hom.: 23

Bravo AF: 0.0119

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.00996 AC: 1209

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	This variant is associated with the following publications: (PMID: 22995991, 20981092, 16257970, 15858711) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PEX26: BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Peroxisome biogenesis disorder 7A (Zellweger) Benign:1

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. -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T;.;T;.
MetaRNN	Benign	0.0092	T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	0.65	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.054	.;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.83
MPC		0.69
ClinPred		0.021	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.23

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: rs12484657; hg19: chr22-18566288;