7-4789852-C-G

Position:

• chr7-4789852-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014855.3(AP5Z1):​c.1728C>G​(p.Ile576Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,400,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07615802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1728C>G	p.Ile576Met	missense_variant	14/17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1260C>G	p.Ile420Met	missense_variant	13/16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1392C>G	p.Ile464Met	missense_variant	12/15		XP_047277054.1
AP5Z1	NR_157345.1	n.1859C>G		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1728C>G	p.Ile576Met	missense_variant	14/17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000638 AC: 1 AN: 156732 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 83520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000437

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1400458 Hom.: 0 Cov.: 32 AF XY: 0.00000434 AC XY: 3 AN XY: 691074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000504

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.2
DANN	Benign	0.77
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.025
Sift	Benign	0.12	T;.
Sift4G	Benign	0.21	T;.
Polyphen		0.089	B;B
Vest4		0.17
MutPred		0.29		Loss of catalytic residue at L581 (P = 0.0605);Loss of catalytic residue at L581 (P = 0.0605);
MVP		0.048
ClinPred		0.038	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs550686881; hg19: chr7-4829483;