rs73305371

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014855.3(AP5Z1):c.512-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,548,868 control chromosomes in the GnomAD database, including 2,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 1481 hom., cov: 33)

Exomes 𝑓: 0.014 ( 1377 hom. )

Consequence

AP5Z1
NM_014855.3 splice_region, intron

Scores

Splicing: ADA: 0.00003628

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.57

Publications

4 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 (BayesDel_noAF=-0.88).

BP6

Variant 7-4783682-A-G is Benign according to our data. Variant chr7-4783682-A-G is described in ClinVar as Benign. ClinVar VariationId is 360312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
AP5Z1	NM_014855.3 link	c.512-7A>G	splice_region_variant, intron_variant	Intron 4 of 16	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1 link	c.44-7A>G	splice_region_variant, intron_variant	Intron 3 of 15		NP_001351787.1
AP5Z1	NR_157345.1 link	n.605-7A>G	splice_region_variant, intron_variant	Intron 4 of 16
AP5Z1	XM_047421098.1 link	c.176-7A>G	splice_region_variant, intron_variant	Intron 2 of 14		XP_047277054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.512-7A>G		splice_region_variant, intron_variant	Intron 4 of 16		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes

AF:

0.0797

AC:

12123

AN:

152098

Hom.:

1475

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0321

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00663

Gnomad OTH

AF:

0.0675

GnomAD2 exomes

AF:

0.0191

AC:

2945

AN:

154268

AF XY:

0.0156

show subpopulations

Gnomad AFR exome

AF:

0.265

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.00370

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000539

Gnomad NFE exome

AF:

0.00710

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0137

AC:

19151

AN:

1396654

Hom.:

1377

Cov.:

AF XY:

0.0125

AC XY:

8631

AN XY:

688626

show subpopulations

African (AFR)

AF:

0.282

AC:

8907

AN:

31532

American (AMR)

AF:

0.0191

AC:

679

AN:

35602

Ashkenazi Jewish (ASJ)

AF:

0.00371

AC:

AN:

25090

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35684

South Asian (SAS)

AF:

0.00124

AC:

AN:

79168

European-Finnish (FIN)

AF:

0.000663

AC:

AN:

48300

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00731

AC:

7881

AN:

1077686

Other (OTH)

AF:

0.0241

AC:

1398

AN:

57908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

911

1823

2734

3646

4557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.0798

AC:

12148

AN:

152214

Hom.:

1481

Cov.:

AF XY:

0.0760

AC XY:

5655

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.265

AC:

11002

AN:

41530

American (AMR)

AF:

0.0320

AC:

490

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00663

AC:

451

AN:

67982

Other (OTH)

AF:

0.0668

AC:

141

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

469

937

1406

1874

2343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0280

Hom.:

211

Bravo

AF:

0.0921

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 48

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 05, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.22

(source)

DANN

Benign

0.38

PhyloP100

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.012

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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