NM_014855.3:c.628C>A

Variant names:

• chr7-4784209-C-A
• rs773542837
• NM_014855.3:c.628C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014855.3(AP5Z1):​c.628C>A​(p.Pro210Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,428,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P210S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 48

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.628C>A	p.Pro210Thr	missense_variant	Exon 6 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.160C>A	p.Pro54Thr	missense_variant	Exon 5 of 16		NP_001351787.1
AP5Z1	XM_047421098.1	c.292C>A	p.Pro98Thr	missense_variant	Exon 4 of 15		XP_047277054.1
AP5Z1	NR_157345.1	n.721C>A		non_coding_transcript_exon_variant	Exon 6 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.628C>A	p.Pro210Thr	missense_variant	Exon 6 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428382 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 708020

African (AFR) AF: 0.00 AC: 0 AN: 32670

American (AMR) AF: 0.00 AC: 0 AN: 39900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.00 AC: 0 AN: 37788

South Asian (SAS) AF: 0.00 AC: 0 AN: 81440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097910

Other (OTH) AF: 0.00 AC: 0 AN: 59122

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 48 Uncertain:1

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with threonine at codon 210 of the AP5Z1 protein (p.Pro210Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with AP5Z1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		4.7
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.35		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.12
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.41
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs773542837; hg19: chr7-4823840;