7-4790832-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014855.3(AP5Z1):c.2098G>A(p.Val700Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,609,232 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 33)

Exomes 𝑓: 0.022 ( 407 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.51

Publications

10 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005810648).

BP6

Variant 7-4790832-G-A is Benign according to our data. Variant chr7-4790832-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2584/152266) while in subpopulation NFE AF = 0.0257 (1750/67994). AF 95% confidence interval is 0.0247. There are 25 homozygotes in GnomAd4. There are 1215 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.2098G>A	p.Val700Met	missense_variant	Exon 16 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.1630G>A	p.Val544Met	missense_variant	Exon 15 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.1762G>A	p.Val588Met	missense_variant	Exon 14 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.2229G>A		non_coding_transcript_exon_variant	Exon 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.2098G>A	p.Val700Met	missense_variant	Exon 16 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2583

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00434

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0167

AC:

4026

AN:

240454

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00379

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.00599

Gnomad EAS exome

AF:

0.0000562

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.0222

AC:

32387

AN:

1456966

Hom.:

407

Cov.:

AF XY:

0.0217

AC XY:

15694

AN XY:

724336

show subpopulations

African (AFR)

AF:

0.00374

AC:

125

AN:

33396

American (AMR)

AF:

0.0132

AC:

584

AN:

44356

Ashkenazi Jewish (ASJ)

AF:

0.00741

AC:

192

AN:

25924

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39626

South Asian (SAS)

AF:

0.00281

AC:

240

AN:

85260

European-Finnish (FIN)

AF:

0.0290

AC:

1495

AN:

51570

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0257

AC:

28503

AN:

1110808

Other (OTH)

AF:

0.0194

AC:

1172

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2047

4094

6142

8189

10236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0170

AC:

2584

AN:

152266

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41568

American (AMR)

AF:

0.0156

AC:

238

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5172

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0299

AC:

318

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0257

AC:

1750

AN:

67994

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

136

272

408

544

680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0189

Hom.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0206

AC:

172

ExAC

AF:

0.0164

AC:

1986

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Apr 10, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 48

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Nov 17, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

T;T

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

.;D

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

3.5

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.14

Sift

Uncertain

0.014

D;.

Sift4G

Uncertain

0.025

D;.

Polyphen

0.86

P;P

Vest4

0.16

ClinPred

0.016

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.37

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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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