rs150895887

Positions:

• chr22-18078506-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_001127649.3(PEX26):​c.130C>T​(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,571,354 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. L44P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0064 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (12 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.139

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012090355).
• BP6: Variant 22-18078506-C-T is Benign according to our data. Variant chr22-18078506-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195337.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr22-18078506-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00641 (976/152244) while in subpopulation AFR AF= 0.0163 (678/41568). AF 95% confidence interval is 0.0153. There are 5 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.130C>T	p.Leu44Phe	missense_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.130C>T	p.Leu44Phe	missense_variant	2/6		NP_060399.1
PEX26	NM_001199319.2	c.130C>T	p.Leu44Phe	missense_variant	2/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.130C>T	p.Leu44Phe	missense_variant	1/5	1	NM_001127649.3	ENSP00000382648	P1
	ENST00000607927.1	n.379G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00300 AC: 521 AN: 173610 Hom.: 3 AF XY: 0.00258 AC XY: 247 AN XY: 95814

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.00642

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00168 AC: 2386 AN: 1419110 Hom.: 12 Cov.: 31 AF XY: 0.00159 AC XY: 1119 AN XY: 703052

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00750

Gnomad4 ASJ exome AF: 0.00656

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.0000728

Gnomad4 FIN exome AF: 0.0000228

Gnomad4 NFE exome AF: 0.000993

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00641 AC: 976 AN: 152244 Hom.: 5 Cov.: 32 AF XY: 0.00613 AC XY: 456 AN XY: 74426

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00266 Hom.: 1

Bravo AF: 0.00744

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00699 AC: 28

ESP6500EA AF: 0.00127 AC: 10

ExAC AF: 0.00166 AC: 192

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 04, 2015

- -

Peroxisome biogenesis disorder 7A (Zellweger) Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.23	.;T;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.62	T;.;T;.
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	1.3	L;L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	.;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.13	.;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.015	.;B;B;.
Vest4		0.27
MVP		0.65
MPC		0.20
ClinPred		0.0081	T
GERP RS		0.74
Varity_R		0.093
gMVP		0.32

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: rs150895887; hg19: chr22-18561272;