rs186003800

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014855.3(AP5Z1):c.1573A>C(p.Lys525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,592,118 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 0.367

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006429881).

BP6

Variant 7-4788272-A-C is Benign according to our data. Variant chr7-4788272-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412233.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}. Variant chr7-4788272-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000835 (127/152094) while in subpopulation NFE AF= 0.00115 (78/67948). AF 95% confidence interval is 0.000942. There are 3 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.1573A>C	p.Lys525Gln	missense_variant	Exon 12 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.1105A>C	p.Lys369Gln	missense_variant	Exon 11 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.1237A>C	p.Lys413Gln	missense_variant	Exon 10 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.1704A>C		non_coding_transcript_exon_variant	Exon 12 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.1573A>C	p.Lys525Gln	missense_variant	Exon 12 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000622

AC:

132

AN:

212254

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

115950

show subpopulations

Gnomad AFR exome

AF:

0.0000841

Gnomad AMR exome

AF:

0.000774

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000704

Gnomad FIN exome

AF:

0.000165

Gnomad NFE exome

AF:

0.000842

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.000588

AC:

847

AN:

1440024

Hom.:

Cov.:

AF XY:

0.000628

AC XY:

449

AN XY:

714514

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000836

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000964

Gnomad4 FIN exome

AF:

0.000118

Gnomad4 NFE exome

AF:

0.000588

Gnomad4 OTH exome

AF:

0.000807

GnomAD4 genome

AF:

0.000835

AC:

127

AN:

152094

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000584

Hom.:

Bravo

AF:

0.000956

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000459

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 48

Uncertain:5Benign:1

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_014855.3(AP5Z1):c.1573A>C, has been identified in exon 0 of the AP5Z1 gene. The variant is predicted to result in a minor amino acid change from lysine to glutamine at position 525 of the protein (NP_055670.1(AP5Z1):p.(Lys525Gln)). The lysine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.06% (156 hetereozygotes, 0 homozygotes). The variant has been previously described as a Variant of Uncertain Significance (ClinVar). Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. -

Dec 13, 2023

Paris Brain Institute, Inserm - ICM

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Individual has a causal pathogenic homozygous variant in RNASEH2B c.529G>A (p.Ala177Thr) -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the AP5Z1 protein (p.Lys525Gln). This variant is present in population databases (rs186003800, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 412233). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AP5Z1 protein function with a negative predictive value of 80%. 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. -

not specified

Uncertain:1Benign:1

Mar 06, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KIAA0415 c.1573A>C (p.Lys525Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 243546 control chromosomes. c.1573A>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia without strong evidence of causality (e.g. Slabicki_2010, Mereaux_2022). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 20613862, 34983064). ClinVar contains an entry for this variant (Variation ID: 412233). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nov 01, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jun 16, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

DANN

Benign

0.90

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.45

N;.

REVEL

Benign

0.015

Sift

Benign

0.22

T;.

Sift4G

Benign

0.23

T;.

Polyphen

0.051

B;B

Vest4

0.16

MVP

0.014

ClinPred

0.0048

GERP RS

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.080

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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