7-4788272-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_014855.3(AP5Z1):c.1573A>C(p.Lys525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,592,118 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K525E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00084 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 0.367

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006429881).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000835 (127/152094) while in subpopulation NFE AF = 0.00115 (78/67948). AF 95% confidence interval is 0.000942. There are 3 homozygotes in GnomAd4. There are 63 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

BS2

High Homozygotes in GnomAd4 at 3 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.1573A>C	p.Lys525Gln	missense	Exon 12 of 17	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.1105A>C	p.Lys369Gln	missense	Exon 11 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.1704A>C		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.1573A>C	p.Lys525Gln	missense	Exon 12 of 17	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.1573A>C	p.Lys525Gln	missense	Exon 12 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.1642A>C	p.Lys548Gln	missense	Exon 12 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000622

AC:

132

AN:

212254

AF XY:

0.000673

show subpopulations

Gnomad AFR exome

AF:

0.0000841

Gnomad AMR exome

AF:

0.000774

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000165

Gnomad NFE exome

AF:

0.000842

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.000588

AC:

847

AN:

1440024

Hom.:

Cov.:

AF XY:

0.000628

AC XY:

449

AN XY:

714514

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33066

American (AMR)

AF:

0.000836

AC:

AN:

41890

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

38730

South Asian (SAS)

AF:

0.000964

AC:

AN:

82996

European-Finnish (FIN)

AF:

0.000118

AC:

AN:

50756

Middle Eastern (MID)

AF:

0.00513

AC:

AN:

4480

European-Non Finnish (NFE)

AF:

0.000588

AC:

649

AN:

1102934

Other (OTH)

AF:

0.000807

AC:

AN:

59464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

146

194

243

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:

0.000835

AC:

127

AN:

152094

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41514

American (AMR)

AF:

0.000588

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

67948

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000755

Hom.:

Bravo

AF:

0.000956

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000459

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (6)

not specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.024

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

M_CAP

Benign

0.011

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.37

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.45

REVEL

Benign

0.015

Sift

Benign

0.22

Sift4G

Benign

0.23

Polyphen

0.051

Vest4

0.16

MVP

0.014

ClinPred

0.0048

GERP RS

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.080

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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