22-18085172-C-T

Variant names:

• chr22-18085172-C-T
• rs149153003
• NM_001127649.3:c.728C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127649.3(PEX26):​c.728C>T​(p.Ala243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,068 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A243A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (17 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.506
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070671737).
• BP6: Variant 22-18085172-C-T is Benign according to our data. Variant chr22-18085172-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95879.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (233/152284) while in subpopulation SAS AF = 0.0027 (13/4818). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127649.3. 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.728C>T	p.Ala243Val	missense	Exon 4 of 5	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.728C>T	p.Ala243Val	missense	Exon 5 of 6	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.667+1440C>T		intron	N/A	NP_001186248.1	Q7Z412-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.728C>T	p.Ala243Val	missense	Exon 4 of 5	ENSP00000382648.4	Q7Z412-1
	PEX26	ENST00000329627.11	TSL:1	c.728C>T	p.Ala243Val	missense	Exon 5 of 6	ENSP00000331106.5	Q7Z412-1
	PEX26	ENST00000428061.2	TSL:1	c.667+1440C>T		intron	N/A	ENSP00000412441.2	Q7Z412-2

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00263 AC: 662 AN: 251474 AF XY: 0.00280

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00201 AC: 2933 AN: 1461784 Hom.: 17 Cov.: 32 AF XY: 0.00212 AC XY: 1545 AN XY: 727194

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00279 AC: 125 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 373 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00368 AC: 317 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00166 AC: 1844 AN: 1111930

Other (OTH) AF: 0.00358 AC: 216 AN: 60388

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74464

African (AFR) AF: 0.000192 AC: 8 AN: 41562

American (AMR) AF: 0.00105 AC: 16 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00228 Hom.: 2

Bravo AF: 0.00186

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00246 AC: 299

EpiCase AF: 0.00436

EpiControl AF: 0.00332

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.51
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Polyphen		0.037	B
Vest4		0.17
MVP		0.71
MPC		0.17
ClinPred		0.0012	T
GERP RS		-2.0
Varity_R		0.014
gMVP		0.19
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149153003; hg19: chr22-18567938; COSMIC: COSV61604140; COSMIC: COSV61604140;