rs1339701497

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4PP3

The NM_014855.3(AP5Z1):c.1073_1099delGCGGGGACCCGGCCTCTGTGCGGGTGC(p.Arg358_Val366del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,584,508 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R358R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

AP5Z1
NM_014855.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.71

Publications

0 publications found

Variant links:

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

AP5Z1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_014855.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.1073_1099delGCGGGGACCCGGCCTCTGTGCGGGTGC	p.Arg358_Val366del	disruptive_inframe_deletion	Exon 9 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.605_631delGCGGGGACCCGGCCTCTGTGCGGGTGC	p.Arg202_Val210del	disruptive_inframe_deletion	Exon 8 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.737_763delGCGGGGACCCGGCCTCTGTGCGGGTGC	p.Arg246_Val254del	disruptive_inframe_deletion	Exon 7 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.1166_1192delGCGGGGACCCGGCCTCTGTGCGGGTGC		non_coding_transcript_exon_variant	Exon 9 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.1073_1099delGCGGGGACCCGGCCTCTGTGCGGGTGC	p.Arg358_Val366del	disruptive_inframe_deletion	Exon 9 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000101

AC:

AN:

197432

AF XY:

0.00000926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000671

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000838

AC:

AN:

1432286

Hom.:

AF XY:

0.0000113

AC XY:

AN XY:

710640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33082

American (AMR)

AF:

0.0000487

AC:

AN:

41048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25632

East Asian (EAS)

AF:

0.00

AC:

AN:

38526

South Asian (SAS)

AF:

0.0000241

AC:

AN:

82988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000636

AC:

AN:

1100286

Other (OTH)

AF:

0.0000168

AC:

AN:

59380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 29, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 48

Uncertain:1

Apr 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 446845). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant, c.1073_1099del, results in the deletion of 9 amino acid(s) of the AP5Z1 protein (p.Arg358_Val366del), but otherwise preserves the integrity of the reading frame. -

Hereditary spastic paraplegia

Uncertain:1

Mar 03, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.7

Mutation Taster

=64/136

disease causing (long InDel)

(source)

Splicing

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

Publications

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rs1339701497

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over