7-4784347-G-C

Variant names:

• chr7-4784347-G-C
• rs1254332461
• NM_014855.3:c.766G>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.766G>C​(p.Glu256Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. E256K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.828
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

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=0.042645752).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	NM_014855.3	MANE Select	c.766G>C	p.Glu256Gln	missense	Exon 6 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.298G>C	p.Glu100Gln	missense	Exon 5 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.859G>C		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.766G>C	p.Glu256Gln	missense	Exon 6 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.766G>C	p.Glu256Gln	missense	Exon 6 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.766G>C	p.Glu256Gln	missense	Exon 6 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 48 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.0
DANN	Benign	0.86
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.83
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.013
Sift	Benign	0.45	T
Sift4G	Benign	0.55	T
Polyphen		0.035	B
Vest4		0.091
MutPred		0.17		Loss of glycosylation at T260 (P = 0.1467)
MVP		0.014
ClinPred		0.029	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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: rs1254332461; hg19: chr7-4823978;