rs61752112

Variant names:

• chr17-35575913-G-A
• rs61752112
• NM_000286.3:c.949C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35575913-G-A
• chr17-35575913-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000286.3(PEX12):​c.949C>T​(p.Leu317Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX12 NM_000286.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 5.28
• Publications: 1 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 17-35575913-G-A is Pathogenic according to our data. Variant chr17-35575913-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7779.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX12	NM_000286.3	c.949C>T	p.Leu317Phe	missense_variant	Exon 3 of 3	ENST00000225873.9	NP_000277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX12	ENST00000225873.9	c.949C>T	p.Leu317Phe	missense_variant	Exon 3 of 3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2	n.949C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1		ENSP00000466894.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Peroxisomal biogenesis disorder 3b Pathogenic:1

Jun 08, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) Uncertain:1

Jan 13, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.0	M;M
PhyloP100		5.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.89		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.94
MPC		0.76
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.64
Mutation Taster		=41/59	disease causing

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: rs61752112; hg19: chr17-33902932;