rs77890266

Positions:

chr7-4788228-G-A

Variant summary

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

The NM_014855.3(AP5Z1):c.1529G>A(p.Arg510Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,574,254 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R510W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 32)

Exomes 𝑓: 0.021 ( 400 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.11

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=0.0033444464).

BP6

Variant 7-4788228-G-A is Benign according to our data. Variant chr7-4788228-G-A is described in ClinVar as [Benign]. Clinvar id is 240935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4788228-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.016 (2441/152230) while in subpopulation SAS AF= 0.0257 (124/4824). AF 95% confidence interval is 0.0226. There are 34 homozygotes in gnomad4. There are 1159 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP5Z1	NM_014855.3 linkuse as main transcript	c.1529G>A	p.Arg510Gln	missense_variant	12/17	ENST00000649063.2
AP5Z1	NM_001364858.1 linkuse as main transcript	c.1061G>A	p.Arg354Gln	missense_variant	11/16
AP5Z1	XM_047421098.1 linkuse as main transcript	c.1193G>A	p.Arg398Gln	missense_variant	10/15
AP5Z1	NR_157345.1 linkuse as main transcript	n.1660G>A		non_coding_transcript_exon_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2 linkuse as main transcript	c.1529G>A	p.Arg510Gln	missense_variant	12/17		NM_014855.3	P1	O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2441

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0257

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0235

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0181

AC:

3362

AN:

186222

Hom.:

AF XY:

0.0185

AC XY:

1866

AN XY:

100728

show subpopulations

Gnomad AFR exome

AF:

0.00434

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.00595

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0212

AC:

30196

AN:

1422024

Hom.:

400

Cov.:

AF XY:

0.0215

AC XY:

15166

AN XY:

703940

show subpopulations

Gnomad4 AFR exome

AF:

0.00368

Gnomad4 AMR exome

AF:

0.0160

Gnomad4 ASJ exome

AF:

0.0324

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.0229

Gnomad4 FIN exome

AF:

0.00675

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0238

GnomAD4 genome

AF:

0.0160

AC:

2441

AN:

152230

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1159

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00433

Gnomad4 AMR

AF:

0.0179

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0257

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.0235

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0222

Hom.:

Bravo

AF:

0.0172

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00315

AC:

ESP6500EA

AF:

0.0240

AC:

197

ExAC

AF:

0.0146

AC:

1733

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 23, 2019	- -

Hereditary spastic paraplegia 48

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

.;D

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

0.94

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.050

Sift

Benign

0.23

T;.

Sift4G

Benign

0.077

T;.

Polyphen

0.61

P;P

Vest4

0.072

ClinPred

0.010

GERP RS

2.6

Varity_R

0.058

gMVP

0.46

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