rs774832344

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_014855.3(AP5Z1):c.691C>T(p.Arg231Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,600,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.803

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09637657).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000157 (228/1448434) while in subpopulation MID AF = 0.00208 (12/5756). AF 95% confidence interval is 0.0012. There are 1 homozygotes in GnomAdExome4. There are 115 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check.

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.691C>T	p.Arg231Cys	missense	Exon 6 of 17	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.223C>T	p.Arg75Cys	missense	Exon 5 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.784C>T		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.691C>T	p.Arg231Cys	missense	Exon 6 of 17	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.691C>T	p.Arg231Cys	missense	Exon 6 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.691C>T	p.Arg231Cys	missense	Exon 6 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.0000891

AC:

AN:

224536

AF XY:

0.0000979

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000694

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.000157

AC:

228

AN:

1448434

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

115

AN XY:

719286

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33240

American (AMR)

AF:

0.000116

AC:

AN:

42938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25828

East Asian (EAS)

AF:

0.0000768

AC:

AN:

39058

South Asian (SAS)

AF:

0.000179

AC:

AN:

83858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51116

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000163

AC:

180

AN:

1106726

Other (OTH)

AF:

0.000200

AC:

AN:

59914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000164

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41456

American (AMR)

AF:

0.000393

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68010

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000825

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.0000829

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (2)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

0.13

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

M_CAP

Benign

0.052

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

PhyloP100

0.80

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.4

REVEL

Benign

0.052

Sift

Benign

0.059

Sift4G

Benign

0.17

Polyphen

0.99

Vest4

0.18

MVP

0.21

ClinPred

0.080

GERP RS

4.3

Varity_R

0.097

gMVP

0.32

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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