rs764991282

chr7-4791158-C-Achr7-4791158-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.2197C>A(p.Pro733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P733A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

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]

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=0.21905369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.2197C>A	p.Pro733Thr	missense_variant	17/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.1729C>A	p.Pro577Thr	missense_variant	16/16
AP5Z1	XM_047421098.1	c.1861C>A	p.Pro621Thr	missense_variant	15/15
AP5Z1	NR_157345.1	n.2328C>A		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.2197C>A	p.Pro733Thr	missense_variant	17/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458012 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.00063
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.15
Sift	Benign	0.19	T;.
Sift4G	Benign	0.068	T;.
Polyphen		0.98	D;D
Vest4		0.20
MutPred		0.17		Gain of phosphorylation at P733 (P = 0.0318);Gain of phosphorylation at P733 (P = 0.0318);
MVP		0.15
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.33

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: rs764991282; hg19: chr7-4830789;