chr17-35575213-A-T

Variant names:

• chr17-35575213-A-T
• rs541598688
• NM_000286.3:c.*569T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000286.3(PEX12):​c.*569T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 142,270 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX12 NM_000286.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.675
• Publications: 0 publications found

Genes affected

PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

PEX12 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 3A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• peroxisome biogenesis disorder type 3B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000286.3. 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
	PEX12	NM_000286.3	MANE Select	c.*569T>A		3_prime_UTR	Exon 3 of 3	NP_000277.1	O00623

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX12	ENST00000225873.9	TSL:1 MANE Select	c.*569T>A		3_prime_UTR	Exon 3 of 3	ENSP00000225873.3	O00623

Frequencies

GnomAD3 genomes AF: 0.000914 AC: 130 AN: 142270 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000174

Gnomad OTH AF: 0.00156

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2504 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1322

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AF: 0.00 AC: 0 AN: 542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 58

South Asian (SAS) AF: 0.00 AC: 0 AN: 244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1554

Other (OTH) AF: 0.00 AC: 0 AN: 82

GnomAD4 genome AF: 0.000914 AC: 130 AN: 142270 Hom.: 2 Cov.: 32 AF XY: 0.000891 AC XY: 62 AN XY: 69558

African (AFR) AF: 0.0000256 AC: 1 AN: 39100

American (AMR) AF: 0.00 AC: 0 AN: 14062

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 115 AN: 3198

East Asian (EAS) AF: 0.00 AC: 0 AN: 4938

South Asian (SAS) AF: 0.00 AC: 0 AN: 4330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000174 AC: 11 AN: 63226

Other (OTH) AF: 0.00156 AC: 3 AN: 1920

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000808

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 3A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.65
PhyloP100		-0.68

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: rs541598688; hg19: chr17-33902232;