rs186539500

Variant names:

• chr12-7189938-T-C
• rs186539500
• ENST00000420616.6:c.-295T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001131025.2(PEX5):​c.-295T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,476,546 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (32 hom.)
• Consequence: PEX5 NM_001131025.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702
• Publications: 1 publications found

Genes affected

PEX5 (HGNC:9719): (peroxisomal biogenesis factor 5) The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

PEX5 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 2A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peroxisome biogenesis disorder 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• rhizomelic chondrodysplasia punctata type 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022521615).
• BP6: Variant 12-7189938-T-C is Benign according to our data. Variant chr12-7189938-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 310412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1858/152230) while in subpopulation AFR AF = 0.0417 (1734/41536). AF 95% confidence interval is 0.0401. There are 36 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131025.2. 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
	PEX5	NM_001351132.2	MANE Select	c.-17+188T>C		intron	N/A	NP_001338061.1	P50542-1
	PEX5	NM_001131025.2		c.-295T>C		5_prime_UTR	Exon 1 of 16	NP_001124497.1	A0A0S2Z4H1
	PEX5	NM_001300789.3		c.-59T>C		5_prime_UTR	Exon 1 of 16	NP_001287718.2	A0A0S2Z4H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000420616.6	TSL:1	c.-295T>C		5_prime_UTR	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000675855.1	MANE Select	c.-17+188T>C		intron	N/A	ENSP00000502374.1	P50542-1
	PEX5	ENST00000266563.9	TSL:1	c.-17+188T>C		intron	N/A	ENSP00000266563.5	P50542-2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1862 AN: 152112 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00310 AC: 250 AN: 80662 AF XY: 0.00241

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00126 AC: 1663 AN: 1324316 Hom.: 32 Cov.: 31 AF XY: 0.00117 AC XY: 759 AN XY: 651228

African (AFR) AF: 0.0406 AC: 1145 AN: 28214

American (AMR) AF: 0.00448 AC: 79 AN: 17630

Ashkenazi Jewish (ASJ) AF: 0.00384 AC: 86 AN: 22370

East Asian (EAS) AF: 0.00 AC: 0 AN: 33712

South Asian (SAS) AF: 0.0000869 AC: 6 AN: 69080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32974

Middle Eastern (MID) AF: 0.00261 AC: 14 AN: 5356

European-Non Finnish (NFE) AF: 0.000148 AC: 157 AN: 1059896

Other (OTH) AF: 0.00320 AC: 176 AN: 55084

GnomAD4 genome AF: 0.0122 AC: 1858 AN: 152230 Hom.: 36 Cov.: 32 AF XY: 0.0114 AC XY: 852 AN XY: 74450

African (AFR) AF: 0.0417 AC: 1734 AN: 41536

American (AMR) AF: 0.00510 AC: 78 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68000

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00816 Hom.: 4

Bravo AF: 0.0143

ExAC AF: 0.00102 AC: 20

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Peroxisome biogenesis disorder 2A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.7
DANN	Benign	0.92
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.82	T
PhyloP100		-0.70
PROVEAN	Benign	0.58	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.22
ClinPred		0.0020	T
GERP RS		-5.2
PromoterAI		-0.12	Neutral
gMVP		0.33
Mutation Taster		=100/0	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: rs186539500; hg19: chr12-7342534;