7-4783328-G-C

Variant names:

• chr7-4783328-G-C
• rs115454162
• NM_014855.3:c.379G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014855.3(AP5Z1):​c.379G>C​(p.Glu127Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. E127K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.676
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046809077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.379G>C	p.Glu127Gln	missense_variant	Exon 4 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	XM_047421098.1	c.43G>C	p.Glu15Gln	missense_variant	Exon 2 of 15		XP_047277054.1
AP5Z1	NR_157345.1	n.472G>C		non_coding_transcript_exon_variant	Exon 4 of 17
AP5Z1	NM_001364858.1	c.-90G>C		5_prime_UTR_variant	Exon 3 of 16		NP_001351787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.379G>C	p.Glu127Gln	missense_variant	Exon 4 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457498 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724664

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.0000226 AC: 1 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 85750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109978

Other (OTH) AF: 0.00 AC: 0 AN: 60220

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

Jan 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 127 of the AP5Z1 protein (p.Glu127Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. 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 conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.76
DANN	Benign	0.30
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.055	N;N
PhyloP100		0.68
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.36	N;.
REVEL	Benign	0.10
Sift	Benign	0.53	T;.
Sift4G	Benign	0.69	T;.
Polyphen		0.059	B;B
Vest4		0.10
MutPred		0.20		Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);
MVP		0.030
ClinPred		0.038	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.070
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115454162; hg19: chr7-4822959;