12-7189821-G-A

Variant names:

• chr12-7189821-G-A
• rs927673107
• ENST00000420616.6:c.-412G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001131025.2(PEX5):​c.-412G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 982,396 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: PEX5 NM_001131025.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.934
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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+71G>A		intron	N/A	NP_001338061.1	P50542-1
	PEX5	NM_001131025.2		c.-412G>A		5_prime_UTR	Exon 1 of 16	NP_001124497.1	A0A0S2Z4H1
	PEX5	NM_001300789.3		c.-176G>A		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.-412G>A		5_prime_UTR	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000675855.1	MANE Select	c.-17+71G>A		intron	N/A	ENSP00000502374.1	P50542-1
	PEX5	ENST00000266563.9	TSL:1	c.-17+71G>A		intron	N/A	ENSP00000266563.5	P50542-2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000259 AC: 215 AN: 830324 Hom.: 0 Cov.: 11 AF XY: 0.000235 AC XY: 95 AN XY: 404732

African (AFR) AF: 0.000237 AC: 4 AN: 16860

American (AMR) AF: 0.00 AC: 0 AN: 9702

Ashkenazi Jewish (ASJ) AF: 0.0000730 AC: 1 AN: 13704

East Asian (EAS) AF: 0.00 AC: 0 AN: 25696

South Asian (SAS) AF: 0.00 AC: 0 AN: 31546

European-Finnish (FIN) AF: 0.0000382 AC: 1 AN: 26196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2550

European-Non Finnish (NFE) AF: 0.000303 AC: 202 AN: 667254

Other (OTH) AF: 0.000190 AC: 7 AN: 36816

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74268

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000193

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 2A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		0.93
PromoterAI		-0.072	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs927673107; hg19: chr12-7342417;