Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_014855.3(AP5Z1):c.780C>A(p.Thr260Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,597,018 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 5 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.102

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 7-4784361-C-A is Benign according to our data. Variant chr7-4784361-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360318.

BP7

Synonymous conserved (PhyloP=-0.102 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152202) while in subpopulation SAS AF = 0.00664 (32/4822). AF 95% confidence interval is 0.00483. There are 2 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.780C>A	p.Thr260Thr	synonymous	Exon 6 of 17	NP_055670.1
AP5Z1	NM_001364858.1		c.312C>A	p.Thr104Thr	synonymous	Exon 5 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.873C>A		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP5Z1	ENST00000649063.2	MANE Select	c.780C>A	p.Thr260Thr	synonymous	Exon 6 of 17	ENSP00000497815.1
AP5Z1	ENST00000477680.6	TSL:2	n.538C>A		non_coding_transcript_exon	Exon 4 of 14
AP5Z1	ENST00000491375.1	TSL:5	n.635C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00167

AC:

358

AN:

214424

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.0000845

Gnomad AMR exome

AF:

0.000191

Gnomad ASJ exome

AF:

0.00822

Gnomad EAS exome

AF:

0.0000619

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000323

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.000792

AC:

1144

AN:

1444816

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

744

AN XY:

717548

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33298

American (AMR)

AF:

0.000212

AC:

AN:

42378

Ashkenazi Jewish (ASJ)

AF:

0.00785

AC:

203

AN:

25846

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39140

South Asian (SAS)

AF:

0.00769

AC:

646

AN:

84046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48690

Middle Eastern (MID)

AF:

0.00210

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.000186

AC:

206

AN:

1105896

Other (OTH)

AF:

0.00110

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152202

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00664

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

67992

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000423

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (2)

not provided (2)

Hereditary spastic paraplegia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.0

(source)

DANN

Benign

0.74

PhyloP100

-0.10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

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

rs377507553

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