chr22-18078506-C-T

Variant names:

• chr22-18078506-C-T
• rs150895887
• NM_001127649.3:c.130C>T

Variant summary

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

The NM_017929.6(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. 13/21 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_017929.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.139
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 7A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• peroxisome biogenesis disorder 7B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-18078507-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3768062.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 195337.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017929.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	NM_001127649.3	MANE Select	c.130C>T	p.Leu44Phe	missense	Exon 1 of 5	NP_001121121.1
	PEX26	NM_017929.6		c.130C>T	p.Leu44Phe	missense	Exon 2 of 6	NP_060399.1
	PEX26	NM_001199319.2		c.130C>T	p.Leu44Phe	missense	Exon 2 of 5	NP_001186248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.130C>T	p.Leu44Phe	missense	Exon 1 of 5	ENSP00000382648.4
	PEX26	ENST00000329627.11	TSL:1	c.130C>T	p.Leu44Phe	missense	Exon 2 of 6	ENSP00000331106.5
	PEX26	ENST00000428061.2	TSL:1	c.130C>T	p.Leu44Phe	missense	Exon 1 of 4	ENSP00000412441.2

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

GnomAD2 exomes AF: 0.00300 AC: 521 AN: 173610 AF XY: 0.00258

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 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

African (AFR) AF: 0.0167 AC: 547 AN: 32712

American (AMR) AF: 0.00750 AC: 291 AN: 38806

Ashkenazi Jewish (ASJ) AF: 0.00656 AC: 167 AN: 25448

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37598

South Asian (SAS) AF: 0.0000728 AC: 6 AN: 82414

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43854

Middle Eastern (MID) AF: 0.00656 AC: 37 AN: 5638

European-Non Finnish (NFE) AF: 0.000993 AC: 1086 AN: 1093668

Other (OTH) AF: 0.00424 AC: 250 AN: 58972

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

African (AFR) AF: 0.0163 AC: 678 AN: 41568

American (AMR) AF: 0.0112 AC: 172 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67998

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) (2)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder 7A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.14
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.33
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.015	B
Vest4		0.27
MVP		0.65
MPC		0.20
ClinPred		0.0081	T
GERP RS		0.74
PromoterAI		0.31	Neutral
Varity_R		0.093
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs150895887; hg19: chr22-18561272;