rs111358719

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.1369C>T(p.Leu457Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0027 in 1,551,994 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 42 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.73

Publications

1 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=-0.55).

BP6

Variant 7-4787691-C-T is Benign according to our data. Variant chr7-4787691-C-T is described in ClinVar as [Benign]. Clinvar id is 360329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2121/152268) while in subpopulation AFR AF = 0.0481 (1997/41548). AF 95% confidence interval is 0.0463. There are 48 homozygotes in GnomAd4. There are 1040 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.1369C>T	p.Leu457Leu	synonymous_variant	Exon 11 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.901C>T	p.Leu301Leu	synonymous_variant	Exon 10 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.1033C>T	p.Leu345Leu	synonymous_variant	Exon 9 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.1500C>T		non_coding_transcript_exon_variant	Exon 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.1369C>T	p.Leu457Leu	synonymous_variant	Exon 11 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0139

AC:

2116

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00862

GnomAD2 exomes

AF:

0.00337

AC:

529

AN:

157008

AF XY:

0.00252

show subpopulations

Gnomad AFR exome

AF:

0.0510

Gnomad AMR exome

AF:

0.00267

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.00274

GnomAD4 exome

AF:

0.00148

AC:

2070

AN:

1399726

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

871

AN XY:

690948

show subpopulations

African (AFR)

AF:

0.0501

AC:

1591

AN:

31760

American (AMR)

AF:

0.00299

AC:

108

AN:

36108

Ashkenazi Jewish (ASJ)

AF:

0.0000794

AC:

AN:

25200

East Asian (EAS)

AF:

0.00

AC:

AN:

35984

South Asian (SAS)

AF:

0.000176

AC:

AN:

79376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46930

Middle Eastern (MID)

AF:

0.00290

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.000147

AC:

159

AN:

1080740

Other (OTH)

AF:

0.00310

AC:

180

AN:

58112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0139

AC:

2121

AN:

152268

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0481

AC:

1997

AN:

41548

American (AMR)

AF:

0.00490

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68004

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00553

Hom.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.00173

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 20, 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: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. -

not specified

Benign:1

Dec 30, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 17, 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

-0.55

CADD

Benign

6.6

(source)

DANN

Benign

0.56

PhyloP100

3.7

Mutation Taster

=97/3

polymorphism

(source)

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

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rs111358719

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