rs397704705

Positions:

• chr7-4781212-CGGAT-CTGCTGTAAACTGTAACTGTAAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 stop_gained, missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.67

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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. Fraction of 0.967 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is Pathogenic according to our data. Variant chr7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is described in ClinVar as [Pathogenic]. Clinvar id is 2.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained, missense_variant, disruptive_inframe_insertion	2/17		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

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 48 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 29, 2010	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397704705; hg19: chr7-4820844;