rs202169962

chr7-4783439-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014855.3(AP5Z1):c.490A>G(p.Ser164Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,612,644 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (5 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.579

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052919686).
• BP6: Variant 7-4783439-A-G is Benign according to our data. Variant chr7-4783439-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 538868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.490A>G	p.Ser164Gly	missense_variant	4/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.22A>G	p.Ser8Gly	missense_variant	3/16
AP5Z1	XM_047421098.1	c.154A>G	p.Ser52Gly	missense_variant	2/15
AP5Z1	NR_157345.1	n.583A>G		non_coding_transcript_exon_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.490A>G	p.Ser164Gly	missense_variant	4/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 152022 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000887 AC: 220 AN: 248066 Hom.: 3 AF XY: 0.000741 AC XY: 100 AN XY: 134864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0118

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000240 AC: 350 AN: 1460504 Hom.: 5 Cov.: 32 AF XY: 0.000211 AC XY: 153 AN XY: 726558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00776

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152140 Hom.: 1 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000764 Hom.: 0

Bravo AF: 0.000567

ExAC AF: 0.000844 AC: 102

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.019
Sift	Benign	0.35	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.82	P;P
Vest4		0.25
MVP		0.040
ClinPred		0.019	T
GERP RS		2.4
Varity_R		0.035
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs202169962; hg19: chr7-4823070;