12-7189747-C-G

Variant names:

• chr12-7189747-C-G
• rs12227917
• NM_001351132.2:c.-20C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001351132.2(PEX5):​c.-20C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 427,362 control chromosomes in the GnomAD database, including 55,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15767 hom., cov: 32)
  • Exomes 𝑓: 0.53 (40029 hom.)
• Consequence: PEX5 NM_001351132.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226
• Publications: 8 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 (BayesDel_noAF=-0.82).
• BP6: Variant 12-7189747-C-G is Benign according to our data. Variant chr12-7189747-C-G is described in ClinVar as Benign. ClinVar VariationId is 310406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351132.2. 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.-20C>G		5_prime_UTR	Exon 1 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.-20C>G		5_prime_UTR	Exon 1 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.-486C>G		5_prime_UTR	Exon 1 of 16	NP_001124497.1	A0A0S2Z4H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000675855.1	MANE Select	c.-20C>G		5_prime_UTR	Exon 1 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.-486C>G		5_prime_UTR	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266563.9	TSL:1	c.-20C>G		5_prime_UTR	Exon 1 of 15	ENSP00000266563.5	P50542-2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64951 AN: 151756 Hom.: 15755 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.466

GnomAD4 exome AF: 0.531 AC: 146303 AN: 275496 Hom.: 40029 Cov.: 4 AF XY: 0.532 AC XY: 74025 AN XY: 139198

African (AFR) AF: 0.204 AC: 1343 AN: 6594

American (AMR) AF: 0.664 AC: 4411 AN: 6646

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 4468 AN: 8484

East Asian (EAS) AF: 0.422 AC: 8730 AN: 20698

South Asian (SAS) AF: 0.579 AC: 2434 AN: 4206

European-Finnish (FIN) AF: 0.463 AC: 9391 AN: 20298

Middle Eastern (MID) AF: 0.580 AC: 750 AN: 1292

European-Non Finnish (NFE) AF: 0.558 AC: 106509 AN: 190864

Other (OTH) AF: 0.504 AC: 8267 AN: 16414

GnomAD4 genome AF: 0.428 AC: 64978 AN: 151866 Hom.: 15767 Cov.: 32 AF XY: 0.428 AC XY: 31733 AN XY: 74210

African (AFR) AF: 0.196 AC: 8140 AN: 41504

American (AMR) AF: 0.605 AC: 9246 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1749 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2054 AN: 5078

South Asian (SAS) AF: 0.466 AC: 2248 AN: 4822

European-Finnish (FIN) AF: 0.442 AC: 4658 AN: 10546

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.519 AC: 35188 AN: 67852

Other (OTH) AF: 0.462 AC: 975 AN: 2110

Alfa AF: 0.321 Hom.: 854

Bravo AF: 0.431

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.9
DANN	Benign	0.39
PhyloP100		-0.23
PromoterAI		-0.11	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs12227917; hg19: chr12-7342343;