7-4788253-C-G

Variant names:

• chr7-4788253-C-G
• rs77560694
• NM_014855.3:c.1554C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014855.3(AP5Z1):​c.1554C>G​(p.Phe518Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,588,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F518F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.984
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22752151).

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.1554C>G	p.Phe518Leu	missense	Exon 12 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1086C>G	p.Phe362Leu	missense	Exon 11 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.1685C>G		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.1554C>G	p.Phe518Leu	missense	Exon 12 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.1554C>G	p.Phe518Leu	missense	Exon 12 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.1623C>G	p.Phe541Leu	missense	Exon 12 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436300 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712282

African (AFR) AF: 0.00 AC: 0 AN: 32998

American (AMR) AF: 0.00 AC: 0 AN: 41272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38506

South Asian (SAS) AF: 0.00 AC: 0 AN: 82406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4598

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100930

Other (OTH) AF: 0.00 AC: 0 AN: 59342

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 19

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.98
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.053
Sift	Benign	0.075	T
Sift4G	Benign	0.10	T
Polyphen		0.23	B
Vest4		0.23
MutPred		0.63		Gain of disorder (P = 0.0957)
MVP		0.055
ClinPred		0.53	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.56
Mutation Taster		=68/32	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: rs77560694; hg19: chr7-4827884;