chr7-4787729-GCTGCTGGACCTGCC-G

Variant names:

• chr7-4787729-GCTGCTGGACCTGCC-G
• rs397704709
• NM_014855.3:c.1413_1426delGGACCTGCCCTGCT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_014855.3(AP5Z1):​c.1413_1426delGGACCTGCCCTGCT​(p.Leu473GlyfsTer54) variant causes a frameshift 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP5Z1 NM_014855.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.47
• Publications: 1 publications found

Genes affected

AP5Z1 (HGNC:22197): (adaptor related protein complex 5 subunit zeta 1) This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862). [provided by RefSeq, Jan 2011]

AP5Z1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 48

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-4787729-GCTGCTGGACCTGCC-G is Pathogenic according to our data. Variant chr7-4787729-GCTGCTGGACCTGCC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1413_1426delGGACCTGCCCTGCT	p.Leu473GlyfsTer54	frameshift_variant	Exon 11 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.945_958delGGACCTGCCCTGCT	p.Leu317GlyfsTer54	frameshift_variant	Exon 10 of 16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1077_1090delGGACCTGCCCTGCT	p.Leu361GlyfsTer54	frameshift_variant	Exon 9 of 15		XP_047277054.1
AP5Z1	NR_157345.1	n.1544_1557delGGACCTGCCCTGCT		non_coding_transcript_exon_variant	Exon 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1413_1426delGGACCTGCCCTGCT	p.Leu473GlyfsTer54	frameshift_variant	Exon 11 of 17		NM_014855.3	ENSP00000497815.1

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 48 Pathogenic:1

Jun 29, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397704709; hg19: chr7-4827360;