22-18078399-C-T

Position:

chr22-18078399-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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.89

Variant links:

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]

PEX26 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
PEX26	NM_001127649.3 linkuse as main transcript	c.23C>T	p.Ser8Phe	missense_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6 linkuse as main transcript	c.23C>T	p.Ser8Phe	missense_variant	2/6		NP_060399.1
PEX26	NM_001199319.2 linkuse as main transcript	c.23C>T	p.Ser8Phe	missense_variant	2/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8 linkuse as main transcript	c.23C>T	p.Ser8Phe	missense_variant	1/5	1	NM_001127649.3	ENSP00000382648	P1	Q7Z412-1
	ENST00000607927.1 linkuse as main transcript	n.486G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

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:

AN:

213916

Hom.:

AF XY:

0.0000676

AC XY:

AN XY:

118348

show subpopulations

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:

AN:

1447280

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

719212

show subpopulations

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:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

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:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;T;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.73

T;.;T;.

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.4

M;M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

.;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

.;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over