12-7189938-T-C

Position:

• chr12-7189938-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000420616.6(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 ENST00000420616.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.-17+188T>C		intron_variant		ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.-17+188T>C		intron_variant			NM_001351132.2	ENSP00000502374	A1

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

GnomAD3 exomes AF: 0.00310 AC: 250 AN: 80662 Hom.: 6 AF XY: 0.00241 AC XY: 110 AN XY: 45580

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 SAS 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

Gnomad4 AFR exome AF: 0.0406

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.00384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000869

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00320

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

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00732 Hom.: 4

Bravo AF: 0.0143

ExAC AF: 0.00102 AC: 20

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Peroxisome biogenesis disorder 2A (Zellweger) Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	N;N;N;N;N
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
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs186539500; hg19: chr12-7342534;