rs368571200

Positions:

• chr7-4791361-G-A

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.2400G>A​(p.Arg800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000557 in 1,608,042 control chromosomes in the GnomAD database, including 6 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 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (6 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.256

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-4791361-G-A is Benign according to our data. Variant chr7-4791361-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240941.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.256 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.2400G>A	p.Arg800=	synonymous_variant	17/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1932G>A	p.Arg644=	synonymous_variant	16/16		NP_001351787.1
AP5Z1	XM_047421098.1	c.2064G>A	p.Arg688=	synonymous_variant	15/15		XP_047277054.1
AP5Z1	NR_157345.1	n.2531G>A		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.2400G>A	p.Arg800=	synonymous_variant	17/17		NM_014855.3	ENSP00000497815	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000656 AC: 154 AN: 234930 Hom.: 2 AF XY: 0.000888 AC XY: 114 AN XY: 128428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.000870

GnomAD4 exome AF: 0.000578 AC: 842 AN: 1455674 Hom.: 6 Cov.: 32 AF XY: 0.000636 AC XY: 460 AN XY: 723630

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.000765

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74504

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000550 Hom.: 0

Bravo AF: 0.000344

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	- -
Uncertain significance, 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, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AP5Z1: BP4, BP7 -

AP5Z1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This 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). -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.0
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368571200; hg19: chr7-4830992;