rs3031851

Variant names:

• chr17-35575211-TAA-T
• rs3031851
• NM_000286.3:c.*569_*570delTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000286.3(PEX12):​c.*569_*570delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 154,756 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (100 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1 hom.)
• Consequence: PEX12 NM_000286.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0580
• 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 -10 ACMG points.

• BP6: Variant 17-35575211-TAA-T is Benign according to our data. Variant chr17-35575211-TAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 322640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0325 (4947/152078) while in subpopulation SAS AF = 0.0529 (255/4816). AF 95% confidence interval is 0.0476. There are 100 homozygotes in GnomAd4. There are 2373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 100 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.*569_*570delTT		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.*569_*570delTT		3_prime_UTR	Exon 3 of 3	ENSP00000225873.3	O00623

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4937 AN: 151958 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0527

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0306 AC: 82 AN: 2678 Hom.: 1 AF XY: 0.0309 AC XY: 44 AN XY: 1424

African (AFR) AF: 0.125 AC: 1 AN: 8

American (AMR) AF: 0.0172 AC: 10 AN: 580

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 52

South Asian (SAS) AF: 0.0478 AC: 13 AN: 272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0326 AC: 54 AN: 1656

Other (OTH) AF: 0.0435 AC: 4 AN: 92

GnomAD4 genome AF: 0.0325 AC: 4947 AN: 152078 Hom.: 100 Cov.: 32 AF XY: 0.0319 AC XY: 2373 AN XY: 74330

African (AFR) AF: 0.0288 AC: 1197 AN: 41564

American (AMR) AF: 0.0406 AC: 621 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3470

East Asian (EAS) AF: 0.0113 AC: 57 AN: 5054

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4816

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10592

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2430 AN: 67978

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0325 Hom.: 4

Bravo AF: 0.0340

Asia WGS AF: 0.0310 AC: 110 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.058
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: rs3031851; hg19: chr17-33902230;