7-4781717-G-C

Position:

• chr7-4781717-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014855.3(AP5Z1):​c.329G>C​(p.Arg110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.586

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065719604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.329G>C	p.Arg110Pro	missense_variant	3/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.-103+405G>C		intron_variant
AP5Z1	NR_157345.1	n.422G>C		non_coding_transcript_exon_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.329G>C	p.Arg110Pro	missense_variant	3/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239802 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130850

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: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430012 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704310

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.40	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.018
Sift	Benign	0.089	T;.
Sift4G	Benign	0.21	T;.
Polyphen		0.067	B;B
Vest4		0.52
MutPred		0.39		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.067
ClinPred		0.077	T
GERP RS		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201481802; hg19: chr7-4821348;