chr17-35575265-T-C

Variant names:

• chr17-35575265-T-C
• rs1046321
• NM_000286.3:c.*517A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000286.3(PEX12):​c.*517A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 159,382 control chromosomes in the GnomAD database, including 12,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11584 hom., cov: 31)
  • Exomes 𝑓: 0.38 (607 hom.)
• Consequence: PEX12 NM_000286.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.212
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-35575265-T-C is Benign according to our data. Variant chr17-35575265-T-C is described in ClinVar as Benign. ClinVar VariationId is 322645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

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.*517A>G		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.*517A>G		3_prime_UTR	Exon 3 of 3	ENSP00000225873.3	O00623

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57195 AN: 151752 Hom.: 11589 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.380 AC: 2852 AN: 7514 Hom.: 607 Cov.: 0 AF XY: 0.370 AC XY: 1450 AN XY: 3922

African (AFR) AF: 0.242 AC: 16 AN: 66

American (AMR) AF: 0.379 AC: 659 AN: 1738

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 22 AN: 76

East Asian (EAS) AF: 0.295 AC: 109 AN: 370

South Asian (SAS) AF: 0.328 AC: 350 AN: 1066

European-Finnish (FIN) AF: 0.350 AC: 28 AN: 80

Middle Eastern (MID) AF: 0.375 AC: 3 AN: 8

European-Non Finnish (NFE) AF: 0.411 AC: 1573 AN: 3830

Other (OTH) AF: 0.329 AC: 92 AN: 280

GnomAD4 genome AF: 0.377 AC: 57191 AN: 151868 Hom.: 11584 Cov.: 31 AF XY: 0.379 AC XY: 28100 AN XY: 74206

African (AFR) AF: 0.220 AC: 9126 AN: 41418

American (AMR) AF: 0.423 AC: 6441 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3468

East Asian (EAS) AF: 0.361 AC: 1862 AN: 5160

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4820

European-Finnish (FIN) AF: 0.468 AC: 4934 AN: 10542

Middle Eastern (MID) AF: 0.352 AC: 102 AN: 290

European-Non Finnish (NFE) AF: 0.451 AC: 30618 AN: 67928

Other (OTH) AF: 0.381 AC: 801 AN: 2102

Alfa AF: 0.410 Hom.: 1767

Bravo AF: 0.364

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Peroxisome biogenesis disorder 3A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.58
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs1046321; hg19: chr17-33902284;