rs183580097

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014855.3(AP5Z1):c.2230G>A(p.Ala744Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,568 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 21 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.216

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032834113).

BP6

Variant 7-4791191-G-A is Benign according to our data. Variant chr7-4791191-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 417166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4791191-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00576 (877/152364) while in subpopulation AFR AF= 0.0187 (776/41578). AF 95% confidence interval is 0.0176. There are 14 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.2230G>A	p.Ala744Thr	missense_variant	Exon 17 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.1762G>A	p.Ala588Thr	missense_variant	Exon 16 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.1894G>A	p.Ala632Thr	missense_variant	Exon 15 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.2361G>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.2230G>A	p.Ala744Thr	missense_variant	Exon 17 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

872

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00251

AC:

618

AN:

246372

Hom.:

AF XY:

0.00253

AC XY:

339

AN XY:

134254

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00791

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00118

AC:

1729

AN:

1460204

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

726358

show subpopulations

Gnomad4 AFR exome

AF:

0.0197

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00645

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00576

AC:

877

AN:

152364

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

419

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0187

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00621

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00165

Hom.:

Bravo

AF:

0.00668

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.00291

AC:

352

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 16, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 10, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Hereditary spastic paraplegia 48

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jul 14, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.26

DANN

Benign

0.74

DEOGEN2

Benign

0.0096

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.53

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;L

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.64

N;.

REVEL

Benign

0.017

Sift

Benign

0.63

T;.

Sift4G

Benign

0.75

T;.

Polyphen

0.0090

B;B

Vest4

0.077

MVP

0.014

ClinPred

0.000022

GERP RS

-7.3

Varity_R

0.014

gMVP

0.14

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