NM_001351132.2:c.1718+13A>G

Variant names:

• chr12-7209853-A-G
• rs116873137
• NM_001351132.2:c.1718+13A>G

Variant summary

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

The NM_001351132.2(PEX5):​c.1718+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,016 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.017 (268 hom.)
• Consequence: PEX5 NM_001351132.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.89
• Publications: 1 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.84).
• BP6: Variant 12-7209853-A-G is Benign according to our data. Variant chr12-7209853-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257547.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 = 0.0107 (1633/152288) while in subpopulation NFE AF = 0.0185 (1255/68020). AF 95% confidence interval is 0.0176. There are 13 homozygotes in GnomAd4. There are 756 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.1718+13A>G		intron	N/A	NP_001338061.1
	PEX5	NM_001131023.2		c.1763+13A>G		intron	N/A	NP_001124495.1
	PEX5	NM_001131025.2		c.1718+13A>G		intron	N/A	NP_001124497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000675855.1	MANE Select	c.1718+13A>G		intron	N/A	ENSP00000502374.1
	PEX5	ENST00000420616.6	TSL:1	c.1718+13A>G		intron	N/A	ENSP00000410159.2
	PEX5	ENST00000266564.7	TSL:1	c.1694+13A>G		intron	N/A	ENSP00000266564.3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1633 AN: 152170 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0104 AC: 2621 AN: 251348 AF XY: 0.0106

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0168 AC: 24506 AN: 1461728 Hom.: 268 Cov.: 34 AF XY: 0.0164 AC XY: 11897 AN XY: 727154

African (AFR) AF: 0.00263 AC: 88 AN: 33480

American (AMR) AF: 0.00758 AC: 339 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00474 AC: 124 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00327 AC: 282 AN: 86244

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53416

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.0203 AC: 22616 AN: 1111870

Other (OTH) AF: 0.0148 AC: 893 AN: 60394

GnomAD4 genome AF: 0.0107 AC: 1633 AN: 152288 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 756 AN XY: 74466

African (AFR) AF: 0.00303 AC: 126 AN: 41536

American (AMR) AF: 0.0118 AC: 181 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1255 AN: 68020

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0123 Hom.: 4

Bravo AF: 0.0113

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0050
DANN	Benign	0.46
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

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: rs116873137; hg19: chr12-7362449;