rs1554257381

Positions:

• chr7-4781741-T-TTCTC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014855.3(AP5Z1):​c.355_358dup​(p.Leu120SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,570,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.478

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-4781741-T-TTCTC is Pathogenic according to our data. Variant chr7-4781741-T-TTCTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.355_358dup	p.Leu120SerfsTer6	frameshift_variant	3/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.-103+431_-103+434dup		intron_variant			NP_001351787.1
AP5Z1	NR_157345.1	n.448_451dup		non_coding_transcript_exon_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.355_358dup	p.Leu120SerfsTer6	frameshift_variant	3/17		NM_014855.3	ENSP00000497815	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1418456 Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 8 AN XY: 697554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2017	The c.355_358dupCTCT variant in the AP5Z1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.355_358dupCTCT variant causes a frameshift starting with codon Leucine 120, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Leu120SerfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.355_358dupCTCT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.355_358dupCTCT as a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 26, 2017	- -

Hereditary spastic paraplegia 48 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 446850). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu120Serfs*6) in the AP5Z1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP5Z1 are known to be pathogenic (PMID: 20613862, 27606357). -

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: rs1554257381; hg19: chr7-4821372;