ENST00000420616.6:c.-193T>A

Variant names:

• chr12-7190040-T-A
• rs113752912
• ENST00000420616.6:c.-193T>A

Variant summary

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

The ENST00000420616.6(PEX5):​c.-193T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0996 in 1,502,774 control chromosomes in the GnomAD database, including 8,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (651 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7854 hom.)
• Consequence: PEX5 ENST00000420616.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.10
• Publications: 4 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=-0.77).
• BP6: Variant 12-7190040-T-A is Benign according to our data. Variant chr12-7190040-T-A is described in ClinVar as Benign. ClinVar VariationId is 310415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420616.6. 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
	PEX5	NM_001351132.2	MANE Select	c.-17+290T>A		intron	N/A	NP_001338061.1	P50542-1
	PEX5	NM_001131025.2		c.-193T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001124497.1	A0A0S2Z4H1
	PEX5	NM_001131026.2		c.-193T>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001124498.1	P50542-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000420616.6	TSL:1	c.-193T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.-193T>A		5_prime_UTR	Exon 1 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000675855.1	MANE Select	c.-17+290T>A		intron	N/A	ENSP00000502374.1	P50542-1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11793 AN: 152098 Hom.: 653 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.102 AC: 137873 AN: 1350558 Hom.: 7854 Cov.: 33 AF XY: 0.101 AC XY: 67279 AN XY: 666326

African (AFR) AF: 0.0194 AC: 566 AN: 29112

American (AMR) AF: 0.0741 AC: 1702 AN: 22962

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3730 AN: 23314

East Asian (EAS) AF: 0.000309 AC: 11 AN: 35590

South Asian (SAS) AF: 0.0279 AC: 2061 AN: 73784

European-Finnish (FIN) AF: 0.0749 AC: 2490 AN: 33244

Middle Eastern (MID) AF: 0.150 AC: 805 AN: 5372

European-Non Finnish (NFE) AF: 0.113 AC: 120913 AN: 1070712

Other (OTH) AF: 0.0991 AC: 5595 AN: 56468

GnomAD4 genome AF: 0.0774 AC: 11788 AN: 152216 Hom.: 651 Cov.: 32 AF XY: 0.0744 AC XY: 5536 AN XY: 74434

African (AFR) AF: 0.0198 AC: 821 AN: 41560

American (AMR) AF: 0.0863 AC: 1321 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4820

European-Finnish (FIN) AF: 0.0701 AC: 744 AN: 10608

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7854 AN: 67970

Other (OTH) AF: 0.100 AC: 211 AN: 2110

Alfa AF: 0.0996 Hom.: 108

Bravo AF: 0.0786

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.75
DANN	Benign	0.78
PhyloP100		-2.1
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs113752912; hg19: chr12-7342636;