rs367981328

chr7-4785561-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014855.3(AP5Z1):c.1009C>T(p.Arg337Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,610,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.115

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3154042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.1009C>T	p.Arg337Trp	missense_variant	9/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.541C>T	p.Arg181Trp	missense_variant	8/16
AP5Z1	XM_047421098.1	c.673C>T	p.Arg225Trp	missense_variant	7/15
AP5Z1	NR_157345.1	n.1102C>T		non_coding_transcript_exon_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1009C>T	p.Arg337Trp	missense_variant	9/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000499 AC: 12 AN: 240438 Hom.: 0 AF XY: 0.0000685 AC XY: 9 AN XY: 131310

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000301

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000357 AC: 52 AN: 1458432 Hom.: 1 Cov.: 33 AF XY: 0.0000441 AC XY: 32 AN XY: 725358

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000385

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74456

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:2

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	Invitae	Jun 27, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 240932). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. This variant is present in population databases (rs367981328, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 337 of the AP5Z1 protein (p.Arg337Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	0.013
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.013	D;.
Polyphen		1.0	D;D
Vest4		0.59
MVP		0.35
ClinPred		0.82	D
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.36

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: rs367981328; hg19: chr7-4825192;