22-18078399-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127649.3(PEX26):c.23C>T(p.Ser8Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000188 in 1,599,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX26	NM_001127649.3	c.23C>T	p.Ser8Phe	missense_variant	1/5	ENST00000399744.8
PEX26	NM_017929.6	c.23C>T	p.Ser8Phe	missense_variant	2/6
PEX26	NM_001199319.2	c.23C>T	p.Ser8Phe	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX26	ENST00000399744.8	c.23C>T	p.Ser8Phe	missense_variant	1/5	1	NM_001127649.3	P1
	ENST00000607927.1	n.486G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000701 AC: 15 AN: 213916 Hom.: 0 AF XY: 0.0000676 AC XY: 8 AN XY: 118348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000742

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1447280 Hom.: 0 Cov.: 30 AF XY: 0.0000181 AC XY: 13 AN XY: 719212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000278

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000678 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 8 of the PEX26 protein (p.Ser8Phe). This variant is present in population databases (rs749146718, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PEX26-related conditions. ClinVar contains an entry for this variant (Variation ID: 958385). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T;.;T;.
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.46
MutPred		0.45		Loss of phosphorylation at S8 (P = 0.013);Loss of phosphorylation at S8 (P = 0.013);Loss of phosphorylation at S8 (P = 0.013);Loss of phosphorylation at S8 (P = 0.013);
MVP		0.99
MPC		0.22
ClinPred		0.57	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749146718; hg19: chr22-18561165;