dbSNP rs183580097: AP5Z1:p.Ala744Thr (chr7-4791191-G-A) – ACMG Classification: Benign (-20 pts)

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.2230G>A(p.Ala744Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,568 control chromosomes in the GnomAD database, including 35 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A744V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 21 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.216

Publications

3 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

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=0.0032834113).

BP6

Variant 7-4791191-G-A is Benign according to our data. Variant chr7-4791191-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 417166.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 = 0.00576 (877/152364) while in subpopulation AFR AF = 0.0187 (776/41578). AF 95% confidence interval is 0.0176. There are 14 homozygotes in GnomAd4. There are 419 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 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	UniProt
AP5Z1	NM_014855.3	MANE Select	c.2230G>A	p.Ala744Thr	missense	Exon 17 of 17	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.1762G>A	p.Ala588Thr	missense	Exon 16 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.2361G>A		non_coding_transcript_exon	Exon 17 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.2230G>A	p.Ala744Thr	missense	Exon 17 of 17	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.2305G>A	p.Ala769Thr	missense	Exon 18 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.2299G>A	p.Ala767Thr	missense	Exon 17 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

872

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00251

AC:

618

AN:

246372

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00118

AC:

1729

AN:

1460204

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

726358

show subpopulations

African (AFR)

AF:

0.0197

AC:

660

AN:

33474

American (AMR)

AF:

0.00184

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26114

East Asian (EAS)

AF:

0.000126

AC:

AN:

39692

South Asian (SAS)

AF:

0.00645

AC:

556

AN:

86166

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

52262

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000223

AC:

248

AN:

1111722

Other (OTH)

AF:

0.00257

AC:

155

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00576

AC:

877

AN:

152364

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

419

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0187

AC:

776

AN:

41578

American (AMR)

AF:

0.00209

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68036

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00165

Hom.:

Bravo

AF:

0.00668

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.00291

AC:

352

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary spastic paraplegia 48 (2)

Hereditary spastic paraplegia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.26

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0096

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

PhyloP100

-0.22

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.64

REVEL

Benign

0.017

Sift

Benign

0.63

Sift4G

Benign

0.75

Polyphen

0.0090

Vest4

0.077

MVP

0.014

ClinPred

0.000022

GERP RS

-7.3

Varity_R

0.014

gMVP

0.14

Mutation Taster

=98/2

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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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

Computational scores

Splicing

Publications

Other links and lift over