Genetic Variant AP5Z1:p.Ala371Pro (chr7-4785663-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014855.3(AP5Z1):c.1111G>C(p.Ala371Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A371T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.51

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.1111G>C	p.Ala371Pro	missense_variant	Exon 9 of 17	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.643G>C	p.Ala215Pro	missense_variant	Exon 8 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.775G>C	p.Ala259Pro	missense_variant	Exon 7 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.1204G>C		non_coding_transcript_exon_variant	Exon 9 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.1111G>C	p.Ala371Pro	missense_variant	Exon 9 of 17		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000630

AC:

AN:

158854

AF XY:

0.0000116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1391572

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32404

American (AMR)

AF:

0.00

AC:

AN:

38094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24632

East Asian (EAS)

AF:

0.00

AC:

AN:

37020

South Asian (SAS)

AF:

0.00

AC:

AN:

79758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077084

Other (OTH)

AF:

0.00

AC:

AN:

57740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000845

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

6.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.1

D;.

REVEL

Uncertain

0.32

Sift

Benign

0.055

T;.

Sift4G

Benign

0.085

T;.

Polyphen

0.70

P;P

Vest4

0.88

MutPred

0.65

Gain of loop (P = 0.002);Gain of loop (P = 0.002);

MVP

0.092

ClinPred

0.71

GERP RS

4.6

Varity_R

0.67

gMVP

0.80

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over