rs147369435

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014855.3(AP5Z1):c.2287G>A(p.Val763Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,612,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.46

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.2287G>A	p.Val763Met	missense_variant	Exon 17 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.1819G>A	p.Val607Met	missense_variant	Exon 16 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.1951G>A	p.Val651Met	missense_variant	Exon 15 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.2418G>A		non_coding_transcript_exon_variant	Exon 17 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.2287G>A	p.Val763Met	missense_variant	Exon 17 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000113

AC:

AN:

247596

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

134860

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000924

AC:

135

AN:

1460428

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726482

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000773

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.000461

AC:

ESP6500EA

AF:

0.000353

AC:

ExAC

AF:

0.0000991

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2022	- -

Hereditary spastic paraplegia 48

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 30, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 763 of the AP5Z1 protein (p.Val763Met). This variant is present in population databases (rs147369435, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412232). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 29, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2023

Variant summary: KIAA0415 c.2287G>A (p.Val763Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 247596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2287G>A has been reported in the literature in at-least one individual affected with Hereditary Spastic Paraplegia (example: DAmore_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 48. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

N;.

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.73

MVP

0.22

ClinPred

0.44

GERP RS

4.4

Varity_R

0.24

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over