rs11766611

Positions:

• chr7-4790832-G-A
• chr7-4790832-G-C
• chr7-4790832-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014855.3(AP5Z1):​c.2098G>A​(p.Val700Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,609,232 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 33)
  • Exomes 𝑓: 0.022 (407 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.51

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005810648).
• BP6: Variant 7-4790832-G-A is Benign according to our data. Variant chr7-4790832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4790832-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.017 (2584/152266) while in subpopulation NFE AF= 0.0257 (1750/67994). AF 95% confidence interval is 0.0247. There are 25 homozygotes in gnomad4. There are 1215 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.2098G>A	p.Val700Met	missense_variant	16/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1630G>A	p.Val544Met	missense_variant	15/16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1762G>A	p.Val588Met	missense_variant	14/15		XP_047277054.1
AP5Z1	NR_157345.1	n.2229G>A		non_coding_transcript_exon_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.2098G>A	p.Val700Met	missense_variant	16/17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2583 AN: 152148 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0167 AC: 4026 AN: 240454 Hom.: 48 AF XY: 0.0169 AC XY: 2216 AN XY: 131070

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0222 AC: 32387 AN: 1456966 Hom.: 407 Cov.: 32 AF XY: 0.0217 AC XY: 15694 AN XY: 724336

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00741

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0170 AC: 2584 AN: 152266 Hom.: 25 Cov.: 33 AF XY: 0.0163 AC XY: 1215 AN XY: 74446

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0257

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0188 Hom.: 28

Bravo AF: 0.0149

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00318 AC: 13

ESP6500EA AF: 0.0206 AC: 172

ExAC AF: 0.0164 AC: 1986

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2024	- -
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. -

Hereditary spastic paraplegia 48 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	.;D
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;.
Sift4G	Uncertain	0.025	D;.
Polyphen		0.86	P;P
Vest4		0.16
ClinPred		0.016	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs11766611; hg19: chr7-4830463;