7-4788272-A-C

Position:

• chr7-4788272-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014855.3(AP5Z1):​c.1573A>C​(p.Lys525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,592,118 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 0.367

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006429881).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1573A>C	p.Lys525Gln	missense_variant	12/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1105A>C	p.Lys369Gln	missense_variant	11/16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1237A>C	p.Lys413Gln	missense_variant	10/15		XP_047277054.1
AP5Z1	NR_157345.1	n.1704A>C		non_coding_transcript_exon_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1573A>C	p.Lys525Gln	missense_variant	12/17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 151976 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000622 AC: 132 AN: 212254 Hom.: 0 AF XY: 0.000673 AC XY: 78 AN XY: 115950

Gnomad AFR exome AF: 0.0000841

Gnomad AMR exome AF: 0.000774

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000704

Gnomad FIN exome AF: 0.000165

Gnomad NFE exome AF: 0.000842

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000588 AC: 847 AN: 1440024 Hom.: 2 Cov.: 31 AF XY: 0.000628 AC XY: 449 AN XY: 714514

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000836

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000964

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.000588

Gnomad4 OTH exome AF: 0.000807

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152094 Hom.: 3 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74350

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000584 Hom.: 0

Bravo AF: 0.000956

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000459 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:5 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	Dec 13, 2023	Individual has a causal pathogenic homozygous variant in RNASEH2B c.529G>A (p.Ala177Thr) -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the AP5Z1 protein (p.Lys525Gln). This variant is present in population databases (rs186003800, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412233). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AP5Z1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant, NM_014855.3(AP5Z1):c.1573A>C, has been identified in exon 0 of the AP5Z1 gene. The variant is predicted to result in a minor amino acid change from lysine to glutamine at position 525 of the protein (NP_055670.1(AP5Z1):p.(Lys525Gln)). The lysine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.06% (156 hetereozygotes, 0 homozygotes). The variant has been previously described as a Variant of Uncertain Significance (ClinVar). Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2024

Variant summary: KIAA0415 c.1573A>C (p.Lys525Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 243546 control chromosomes. c.1573A>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia without strong evidence of causality (e.g. Slabicki_2010, Mereaux_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 48. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20613862, 34983064). ClinVar contains an entry for this variant (Variation ID: 412233). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 16, 2020

- -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.1
DANN	Benign	0.90
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.015
Sift	Benign	0.22	T;.
Sift4G	Benign	0.23	T;.
Polyphen		0.051	B;B
Vest4		0.16
MVP		0.014
ClinPred		0.0048	T
GERP RS		0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs186003800; hg19: chr7-4827903; COSMIC: COSV62240847; COSMIC: COSV62240847;