rs988434253

chr7-4784287-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014855.3(AP5Z1):c.706C>T(p.Gln236Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.46

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 12 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 7-4784287-C-T is Pathogenic according to our data. Variant chr7-4784287-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 578441.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.706C>T	p.Gln236Ter	stop_gained	6/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.238C>T	p.Gln80Ter	stop_gained	5/16
AP5Z1	XM_047421098.1	c.370C>T	p.Gln124Ter	stop_gained	4/15
AP5Z1	NR_157345.1	n.799C>T		non_coding_transcript_exon_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.706C>T	p.Gln236Ter	stop_gained	6/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 48 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in AP5Z1 are known to be pathogenic (PMID: 20613862, 27606357). This variant has not been reported in the literature in individuals with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578441). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln236*) in the AP5Z1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.20
GERP RS		4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs988434253; hg19: chr7-4823918;