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7-4789918-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_014855.3(AP5Z1):c.1794C>T(p.Ala598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,545,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A598A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.43
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-4789918-C-T is Benign according to our data. Variant chr7-4789918-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360337.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.43 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AP5Z1NM_014855.3 linkuse as main transcriptc.1794C>T p.Ala598= synonymous_variant 14/17 ENST00000649063.2
AP5Z1NM_001364858.1 linkuse as main transcriptc.1326C>T p.Ala442= synonymous_variant 13/16
AP5Z1XM_047421098.1 linkuse as main transcriptc.1458C>T p.Ala486= synonymous_variant 12/15
AP5Z1NR_157345.1 linkuse as main transcriptn.1925C>T non_coding_transcript_exon_variant 14/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AP5Z1ENST00000649063.2 linkuse as main transcriptc.1794C>T p.Ala598= synonymous_variant 14/17 NM_014855.3 P1O43299-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000434
AC:
66
AN:
152070
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000580
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000765
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000361
AC:
54
AN:
149412
Hom.:
0
AF XY:
0.000314
AC XY:
25
AN XY:
79648
show subpopulations
Gnomad AFR exome
AF:
0.000128
Gnomad AMR exome
AF:
0.000244
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000918
Gnomad SAS exome
AF:
0.0000445
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000775
Gnomad OTH exome
AF:
0.000237
GnomAD4 exome
AF:
0.000551
AC:
768
AN:
1393610
Hom.:
0
Cov.:
32
AF XY:
0.000514
AC XY:
353
AN XY:
686910
show subpopulations
Gnomad4 AFR exome
AF:
0.000190
Gnomad4 AMR exome
AF:
0.000281
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000560
Gnomad4 SAS exome
AF:
0.000266
Gnomad4 FIN exome
AF:
0.0000212
Gnomad4 NFE exome
AF:
0.000645
Gnomad4 OTH exome
AF:
0.000589
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000434
AC:
66
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.000323
AC XY:
24
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000765
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 06, 2023- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 20, 2020- -
AP5Z1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 19, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
Cadd
Benign
6.7
Dann
Benign
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374673921; hg19: chr7-4829549; API