rs200413804

Variant names:

• chr17-35576125-G-A
• rs200413804
• NM_000286.3:c.737C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35576125-G-A
• chr17-35576125-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000286.3(PEX12):​c.737C>T​(p.Ser246Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S246Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX12 NM_000286.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3281505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX12	NM_000286.3	c.737C>T	p.Ser246Phe	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.737C>T	p.Ser246Phe	missense_variant	Exon 3 of 3	1	NM_000286.3	ENSP00000225873.3
PEX12	ENST00000586663.2	n.737C>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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		5.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.91	N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.021	D;.
Sift4G	Uncertain	0.027	D;D
Polyphen		0.0040	B;B
Vest4		0.42
MutPred		0.56		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.82
MPC		0.21
ClinPred		0.90	D
GERP RS		3.1
Varity_R		0.47
gMVP		0.74

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: rs200413804; hg19: chr17-33903144;