dbSNP rs11549839: AP5Z1:p.Ser94Cys (chr7-4781669-C-G) – 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.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: 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=0.0061022043).

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

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.281C>G	p.Ser94Cys	missense	Exon 3 of 17	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.-103+357C>G		intron	N/A	NP_001351787.1
AP5Z1	NR_157345.1		n.374C>G		non_coding_transcript_exon	Exon 3 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.281C>G	p.Ser94Cys	missense	Exon 3 of 17	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.281C>G	p.Ser94Cys	missense	Exon 3 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.281C>G	p.Ser94Cys	missense	Exon 3 of 17	ENSP00000535695.1

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (2)

not provided (2)

not specified (2)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

0.018

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

PhyloP100

3.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

REVEL

Benign

0.064

Sift

Benign

0.18

Sift4G

Benign

0.23

Polyphen

0.064

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over