NM_014855.3:c.281C>G

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.281C>G(p.Ser94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,602,760 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S94S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 32 hom., cov: 33)

Exomes 𝑓: 0.021 ( 422 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

Publications

7 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=0.0061022043).

BP6

Variant 7-4781669-C-G is Benign according to our data. Variant chr7-4781669-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.016 (2437/152362) while in subpopulation SAS AF = 0.0252 (122/4834). AF 95% confidence interval is 0.0226. There are 32 homozygotes in GnomAd4. There are 1153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.281C>G	p.Ser94Cys	missense_variant	Exon 3 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NR_157345.1 link	n.374C>G		non_coding_transcript_exon_variant	Exon 3 of 17
AP5Z1	NM_001364858.1 link	c.-103+357C>G		intron_variant	Intron 2 of 15		NP_001351787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.281C>G	p.Ser94Cys	missense_variant	Exon 3 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2439

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0173

AC:

4250

AN:

245016

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00633

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0213

AC:

30874

AN:

1450398

Hom.:

422

Cov.:

AF XY:

0.0216

AC XY:

15531

AN XY:

719112

show subpopulations

African (AFR)

AF:

0.00375

AC:

125

AN:

33302

American (AMR)

AF:

0.0150

AC:

669

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

844

AN:

26038

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39354

South Asian (SAS)

AF:

0.0228

AC:

1960

AN:

86048

European-Finnish (FIN)

AF:

0.00677

AC:

353

AN:

52114

Middle Eastern (MID)

AF:

0.0488

AC:

280

AN:

5738

European-Non Finnish (NFE)

AF:

0.0229

AC:

25224

AN:

1103510

Other (OTH)

AF:

0.0237

AC:

1417

AN:

59758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1759

3518

5278

7037

8796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

962

1924

2886

3848

4810

<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:

0.0160

AC:

2437

AN:

152362

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1153

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41578

American (AMR)

AF:

0.0178

AC:

273

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0252

AC:

122

AN:

4834

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0235

AC:

1602

AN:

68040

Other (OTH)

AF:

0.0236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

134

268

403

537

671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0211

Hom.:

Bravo

AF:

0.0172

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00281

AC:

ESP6500EA

AF:

0.0245

AC:

208

ExAC

AF:

0.0171

AC:

2076

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0284

EpiControl

AF:

0.0272

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

Feb 20, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Hereditary spastic paraplegia 48

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Aug 30, 2021

GeneDx

Significance:Likely 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

- -

Hereditary spastic paraplegia

Benign:1

Oct 09, 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

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

0.018

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

3.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.064

Sift

Benign

0.18

T;.

Sift4G

Benign

0.23

T;.

Polyphen

0.064

B;B

Vest4

0.19

ClinPred

0.015

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.23

Mutation Taster

=87/13

polymorphism (auto)

(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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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