rs145760932

Variant names:

• chr12-7210243-G-C
• rs145760932
• NM_001351132.2:c.*20G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-7210243-G-C
• chr12-7210243-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001131026.2(PEX5):​c.*19+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000971 in 1,609,964 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: PEX5 NM_001131026.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9717
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.88
• 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: Benign. The variant received -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 12-7210243-G-C is Benign according to our data. Variant chr12-7210243-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 257545.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 = 0.0048 (731/152294) while in subpopulation AFR AF = 0.0165 (687/41554). AF 95% confidence interval is 0.0155. There are 4 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131026.2. 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.*20G>C		3_prime_UTR	Exon 16 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.*20G>C		3_prime_UTR	Exon 16 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.*20G>C		3_prime_UTR	Exon 16 of 16	NP_001124497.1	A0A0S2Z4H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000675855.1	MANE Select	c.*20G>C		3_prime_UTR	Exon 16 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.*20G>C		3_prime_UTR	Exon 16 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.*20G>C		3_prime_UTR	Exon 15 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00151 AC: 376 AN: 249744 AF XY: 0.000961

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000571 AC: 832 AN: 1457670 Hom.: 5 Cov.: 31 AF XY: 0.000480 AC XY: 348 AN XY: 725478

African (AFR) AF: 0.0168 AC: 561 AN: 33400

American (AMR) AF: 0.00165 AC: 74 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1108728

Other (OTH) AF: 0.00123 AC: 74 AN: 60254

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74462

African (AFR) AF: 0.0165 AC: 687 AN: 41554

American (AMR) AF: 0.00157 AC: 24 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00286 Hom.: 2

Bravo AF: 0.00544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.6
DANN	Uncertain	0.99
PhyloP100		4.9
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145760932; hg19: chr12-7362839; COSMIC: COSV99030493; COSMIC: COSV99030493;