12-7190262-G-A

Variant names:

• chr12-7190262-G-A
• rs74926388
• NM_001351132.2:c.-16-100G>A

Variant summary

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

The NM_001374647.2(PEX5):​c.-116G>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 0.0313 in 1,591,844 control chromosomes in the GnomAD database, including 926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (78 hom., cov: 32)
  • Exomes 𝑓: 0.032 (848 hom.)
• Consequence: PEX5 NM_001374647.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.121

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-7190262-G-A is Benign according to our data. Variant chr12-7190262-G-A is described in ClinVar as [Benign]. Clinvar id is 1291393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0273 (4163/152268) while in subpopulation NFE AF = 0.0371 (2521/68000). AF 95% confidence interval is 0.0359. There are 78 homozygotes in GnomAd4. There are 2146 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.-16-100G>A		intron_variant	Intron 1 of 15	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.-16-100G>A		intron_variant	Intron 1 of 15		NM_001351132.2	ENSP00000502374.1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4166 AN: 152150 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0382

GnomAD4 exome AF: 0.0317 AC: 45601 AN: 1439576 Hom.: 848 Cov.: 30 AF XY: 0.0313 AC XY: 22446 AN XY: 716728

Gnomad4 AFR exome AF: 0.00529 AC: 176 AN: 33272

Gnomad4 AMR exome AF: 0.0224 AC: 1000 AN: 44692

Gnomad4 ASJ exome AF: 0.0313 AC: 815 AN: 26064

Gnomad4 EAS exome AF: 0.0000757 AC: 3 AN: 39630

Gnomad4 SAS exome AF: 0.0133 AC: 1141 AN: 85872

Gnomad4 FIN exome AF: 0.0564 AC: 2329 AN: 41324

Gnomad4 NFE exome AF: 0.0345 AC: 38124 AN: 1104430

Gnomad4 Remaining exome AF: 0.0297 AC: 1778 AN: 59888

GnomAD4 genome AF: 0.0273 AC: 4163 AN: 152268 Hom.: 78 Cov.: 32 AF XY: 0.0288 AC XY: 2146 AN XY: 74446

Gnomad4 AFR AF: 0.00570 AC: 0.00570178 AN: 0.00570178

Gnomad4 AMR AF: 0.0311 AC: 0.0310908 AN: 0.0310908

Gnomad4 ASJ AF: 0.0277 AC: 0.0276817 AN: 0.0276817

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00974 AC: 0.00973891 AN: 0.00973891

Gnomad4 FIN AF: 0.0641 AC: 0.0641026 AN: 0.0641026

Gnomad4 NFE AF: 0.0371 AC: 0.0370735 AN: 0.0370735

Gnomad4 OTH AF: 0.0378 AC: 0.037843 AN: 0.037843

Alfa AF: 0.0326 Hom.: 12

Bravo AF: 0.0239

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs74926388; hg19: chr12-7342858;