6-143451036-CCTAAAGATGCTGAGGT-C

Variant names:

• chr6-143451036-CCTAAAGATGCTGAGGT-C
• NM_003630.3:c.-4_12delAAAGATGCTGAGGTCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003630.3(PEX3):​c.-4_12delAAAGATGCTGAGGTCT​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX3 NM_003630.3 frameshift, start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65

Genes affected

PEX3 (HGNC:8858): (peroxisomal biogenesis factor 3) The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PP5: Variant 6-143451036-CCTAAAGATGCTGAGGT-C is Pathogenic according to our data. Variant chr6-143451036-CCTAAAGATGCTGAGGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3593211.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX3	NM_003630.3	c.-4_12delAAAGATGCTGAGGTCT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 12	ENST00000367591.5	NP_003621.1
PEX3	NM_003630.3	c.-4_12delAAAGATGCTGAGGTCT		5_prime_UTR_variant	Exon 1 of 12	ENST00000367591.5	NP_003621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX3	ENST00000367591.5	c.-4_12delAAAGATGCTGAGGTCT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4
PEX3	ENST00000367591.5	c.-4_12delAAAGATGCTGAGGTCT		5_prime_UTR_variant	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4
PEX3	ENST00000367592.5	c.-4_12delAAAGATGCTGAGGTCT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 7	5		ENSP00000356564.1
PEX3	ENST00000367592.5	c.-4_12delAAAGATGCTGAGGTCT		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000356564.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 10A (Zellweger);C4479254:Peroxisome biogenesis disorder 10B Pathogenic:1

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

hg19: chr6-143772173;