7-4788227-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_014855.3(AP5Z1):c.1528C>T(p.Arg510Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,573,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R510Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.53

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: 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035349816).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000624 (95/152152) while in subpopulation AFR AF = 0.00174 (72/41450). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1528C>T	p.Arg510Trp	missense	Exon 12 of 17	NP_055670.1
AP5Z1	NM_001364858.1		c.1060C>T	p.Arg354Trp	missense	Exon 11 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.1659C>T		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.1528C>T	p.Arg510Trp	missense	Exon 12 of 17	ENSP00000497815.1
AP5Z1	ENST00000865634.1		c.1528C>T	p.Arg510Trp	missense	Exon 12 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.1597C>T	p.Arg533Trp	missense	Exon 12 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000194

AC:

AN:

185682

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00109

Gnomad AMR exome

AF:

0.000392

Gnomad ASJ exome

AF:

0.000113

Gnomad EAS exome

AF:

0.0000739

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.000414

GnomAD4 exome

AF:

0.000128

AC:

182

AN:

1421618

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

703660

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

32564

American (AMR)

AF:

0.000564

AC:

AN:

39016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25408

East Asian (EAS)

AF:

0.000666

AC:

AN:

37512

South Asian (SAS)

AF:

0.0000741

AC:

AN:

80966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49734

Middle Eastern (MID)

AF:

0.000425

AC:

AN:

4702

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1092896

Other (OTH)

AF:

0.000323

AC:

AN:

58820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000624

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

41450

American (AMR)

AF:

0.000916

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000329

Hom.:

Bravo

AF:

0.000665

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000177

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary spastic paraplegia 48 (2)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.8

PhyloP100

2.5

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.62

MVP

0.24

ClinPred

0.12

GERP RS

3.6

Varity_R

0.29

gMVP

0.59

Mutation Taster

=43/57

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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