rs115338343

Variant names:

• chr12-7209754-G-A
• rs115338343
• NM_001351132.2:c.1632G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-7209754-G-A
• chr12-7209754-G-C
• chr12-7209754-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001351132.2(PEX5):​c.1632G>A​(p.Ala544Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,571,076 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (8 hom.)
• Consequence: PEX5 NM_001351132.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.53
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-7209754-G-A is Benign according to our data. Variant chr12-7209754-G-A is described in ClinVar as Benign. ClinVar VariationId is 257546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (950/119090) while in subpopulation AFR AF = 0.0272 (883/32448). AF 95% confidence interval is 0.0257. There are 8 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.1632G>A	p.Ala544Ala	synonymous	Exon 15 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.1677G>A	p.Ala559Ala	synonymous	Exon 15 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.1632G>A	p.Ala544Ala	synonymous	Exon 15 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.1632G>A	p.Ala544Ala	synonymous	Exon 15 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.1632G>A	p.Ala544Ala	synonymous	Exon 15 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.1608G>A	p.Ala536Ala	synonymous	Exon 14 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 956 AN: 119014 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00261

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00102

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00382

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.00954

GnomAD2 exomes AF: 0.00197 AC: 496 AN: 251466 AF XY: 0.00141

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000909 AC: 1320 AN: 1451986 Hom.: 8 Cov.: 34 AF XY: 0.000777 AC XY: 561 AN XY: 722322

African (AFR) AF: 0.0220 AC: 731 AN: 33210

American (AMR) AF: 0.00185 AC: 82 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.000283 AC: 11 AN: 38886

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86168

European-Finnish (FIN) AF: 0.000228 AC: 12 AN: 52642

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5720

European-Non Finnish (NFE) AF: 0.000342 AC: 378 AN: 1105560

Other (OTH) AF: 0.00156 AC: 93 AN: 59658

GnomAD4 genome AF: 0.00798 AC: 950 AN: 119090 Hom.: 8 Cov.: 32 AF XY: 0.00833 AC XY: 482 AN XY: 57880

African (AFR) AF: 0.0272 AC: 883 AN: 32448

American (AMR) AF: 0.00252 AC: 29 AN: 11486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2802

East Asian (EAS) AF: 0.00103 AC: 4 AN: 3898

South Asian (SAS) AF: 0.00 AC: 0 AN: 3634

European-Finnish (FIN) AF: 0.000129 AC: 1 AN: 7740

Middle Eastern (MID) AF: 0.00413 AC: 1 AN: 242

European-Non Finnish (NFE) AF: 0.000312 AC: 17 AN: 54518

Other (OTH) AF: 0.00939 AC: 15 AN: 1598

Alfa AF: 0.00298 Hom.: 5

Bravo AF: 0.00695

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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	-0.93
CADD	Benign	0.042
DANN	Benign	0.58
PhyloP100		-8.5
Mutation Taster		=98/2	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: rs115338343; hg19: chr12-7362350;