rs117666541

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014855.3(AP5Z1):c.1197G>A(p.Glu399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,613,778 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.021 ( 417 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.76

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 7-4786314-G-A is Benign according to our data. Variant chr7-4786314-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.76 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0159 (2425/152328) while in subpopulation SAS AF= 0.0249 (120/4824). AF 95% confidence interval is 0.0224. There are 33 homozygotes in gnomad4. There are 1148 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP5Z1	NM_014855.3 linkuse as main transcript	c.1197G>A	p.Glu399=	synonymous_variant	10/17	ENST00000649063.2
AP5Z1	NM_001364858.1 linkuse as main transcript	c.729G>A	p.Glu243=	synonymous_variant	9/16
AP5Z1	XM_047421098.1 linkuse as main transcript	c.861G>A	p.Glu287=	synonymous_variant	8/15
AP5Z1	NR_157345.1 linkuse as main transcript	n.1290G>A		non_coding_transcript_exon_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2 linkuse as main transcript	c.1197G>A	p.Glu399=	synonymous_variant	10/17		NM_014855.3	P1	O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2425

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0174

AC:

4339

AN:

248912

Hom.:

AF XY:

0.0181

AC XY:

2444

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0223

Gnomad FIN exome

AF:

0.00641

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0212

AC:

30926

AN:

1461450

Hom.:

417

Cov.:

AF XY:

0.0215

AC XY:

15613

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00373

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.0324

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0229

Gnomad4 FIN exome

AF:

0.00685

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0159

AC:

2425

AN:

152328

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1148

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00426

Gnomad4 AMR

AF:

0.0179

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0249

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.0234

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0214

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0274

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 23, 2019	- -

Hereditary spastic paraplegia 48

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

Cadd

Benign

0.43

Dann

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over