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.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. 14/21 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

Publications

9 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=0.0033444464).

BP6

Variant 7-4788228-G-A is Benign according to our data. Variant chr7-4788228-G-A is described in ClinVar as Benign. ClinVar VariationId is 240935.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 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP5Z1	NM_014855.3	MANE Select	c.1529G>A	p.Arg510Gln	missense	Exon 12 of 17	NP_055670.1
AP5Z1	NM_001364858.1		c.1061G>A	p.Arg354Gln	missense	Exon 11 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.1660G>A		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP5Z1	ENST00000649063.2	MANE Select	c.1529G>A	p.Arg510Gln	missense	Exon 12 of 17	ENSP00000497815.1
AP5Z1	ENST00000650581.1		c.329G>A	p.Arg110Gln	missense	Exon 3 of 7	ENSP00000497156.1
AP5Z1	ENST00000469614.1	TSL:2	n.3G>A		non_coding_transcript_exon	Exon 1 of 4

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

GnomAD2 exomes

AF:

0.0181

AC:

3362

AN:

186222

AF XY:

0.0185

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 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

African (AFR)

AF:

0.00368

AC:

120

AN:

32572

American (AMR)

AF:

0.0160

AC:

624

AN:

39098

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

824

AN:

25430

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37512

South Asian (SAS)

AF:

0.0229

AC:

1851

AN:

81002

European-Finnish (FIN)

AF:

0.00675

AC:

336

AN:

49778

Middle Eastern (MID)

AF:

0.0485

AC:

227

AN:

4678

European-Non Finnish (NFE)

AF:

0.0227

AC:

24811

AN:

1093136

Other (OTH)

AF:

0.0238

AC:

1402

AN:

58818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1769

3537

5306

7074

8843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

944

1888

2832

3776

4720

<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:

2441

AN:

152230

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1159

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41558

American (AMR)

AF:

0.0179

AC:

274

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.0257

AC:

124

AN:

4824

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0235

AC:

1599

AN:

67980

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

119

238

358

477

596

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:

0.0200

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (2)

not specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

REVEL

Benign

0.050

Sift

Benign

0.23

Sift4G

Benign

0.077

Polyphen

0.61

Vest4

0.072

ClinPred

0.010

GERP RS

2.6

Varity_R

0.058

gMVP

0.46

Mutation Taster

=97/3

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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rs77890266

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over