rs182411153

Positions:

• chr7-4788262-G-A
• chr7-4788262-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014855.3(AP5Z1):​c.1563G>A​(p.Leu521Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,590,558 control chromosomes in the GnomAD database, including 4 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 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.562

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 7-4788262-G-A is Benign according to our data. Variant chr7-4788262-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417161.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr7-4788262-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.562 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1563G>A	p.Leu521Leu	synonymous_variant	12/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1095G>A	p.Leu365Leu	synonymous_variant	11/16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1227G>A	p.Leu409Leu	synonymous_variant	10/15		XP_047277054.1
AP5Z1	NR_157345.1	n.1694G>A		non_coding_transcript_exon_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1563G>A	p.Leu521Leu	synonymous_variant	12/17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000391 AC: 82 AN: 209470 Hom.: 0 AF XY: 0.000377 AC XY: 43 AN XY: 114170

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.000380

GnomAD4 exome AF: 0.000268 AC: 385 AN: 1438310 Hom.: 4 Cov.: 31 AF XY: 0.000269 AC XY: 192 AN XY: 713514

Gnomad4 AFR exome AF: 0.00557

Gnomad4 AMR exome AF: 0.000889

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000968

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000853

Gnomad4 OTH exome AF: 0.000858

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74432

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.00159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 30, 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, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.7
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs182411153; hg19: chr7-4827893;