NM_000288.4:c.509_511delGTT

Variant names:

• chr6-136846160-GGTT-G
• rs62653608
• NM_000288.4:c.509_511delGTT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_000288.4(PEX7):​c.509_511delGTT​(p.Cys170del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX7 NM_000288.4 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.44
• Publications: 0 publications found

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one 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 have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

PEX7 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 9B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhizomelic chondrodysplasia punctata type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• adult Refsum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000288.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-136846160-GGTT-G is Pathogenic according to our data. Variant chr6-136846160-GGTT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2677734.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4	c.509_511delGTT	p.Cys170del	disruptive_inframe_deletion	Exon 5 of 10	ENST00000318471.5	NP_000279.1
PEX7	NM_001410945.1	c.395_397delGTT	p.Cys132del	disruptive_inframe_deletion	Exon 5 of 10		NP_001397874.1
PEX7	XM_047418874.1	c.509_511delGTT	p.Cys170del	disruptive_inframe_deletion	Exon 5 of 6		XP_047274830.1
PEX7	XM_006715502.3	c.339+19695_339+19697delGTT		intron_variant	Intron 3 of 6		XP_006715565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.509_511delGTT	p.Cys170del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_000288.4	ENSP00000315680.3

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:1

Nov 30, 2021

Baylor 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		7.4
Mutation Taster		=11/89	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: rs62653608; hg19: chr6-137167298;