rs397704705

Variant names:

• chr7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA
• rs397704705
• NM_014855.3:c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_014855.3(AP5Z1):​c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA​(p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn) variant causes a stop gained, missense, disruptive inframe insertion change. 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 INS_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: 33)
• Consequence: AP5Z1 NM_014855.3 stop_gained, missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.67
• Publications: 2 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: Pathogenic. The variant received 16 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 55 pathogenic variants in the truncated region.
• PP5: Variant 7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is Pathogenic according to our data. Variant chr7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained, missense_variant, disruptive_inframe_insertion	Exon 2 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NR_157345.1	n.173_176delGGATinsTGCTGTAAACTGTAACTGTAAA		non_coding_transcript_exon_variant	Exon 2 of 17
AP5Z1	NM_001364858.1	c.-202_-199delGGATinsTGCTGTAAACTGTAACTGTAAA		5_prime_UTR_variant	Exon 2 of 16		NP_001351787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained, missense_variant, disruptive_inframe_insertion	Exon 2 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Pathogenic:2

Jun 29, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular dystrophy with or without extraocular features Pathogenic:1

Dec 17, 2024

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This change likely results in a nonsense-mediated mRNA decay. It is not present in gnomAD v2.1.1 and was previously observed in individuals with complicated spastic paraplegia (reported in ClinVar). It was identified in an affected individual with macular dystrophy, without extraocular features. This variant was classified as Likely pathogenic based on ACMG criteria: PVS1_vstrong, PM2_mod. -

not provided Pathogenic:1

Jun 25, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. This variant appears to segregate with disease associated with this gene in at least one family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

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

Other links and lift over

dbSNP: rs397704705; hg19: chr7-4820844;