rs146665638

Positions:

• chr7-4783765-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014855.3(AP5Z1):​c.588C>T​(p.Ser196=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,550,482 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.20

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-4783765-C-T is Benign according to our data. Variant chr7-4783765-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4783765-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.2 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.588C>T	p.Ser196=	synonymous_variant	5/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.120C>T	p.Ser40=	synonymous_variant	4/16
AP5Z1	XM_047421098.1	c.252C>T	p.Ser84=	synonymous_variant	3/15
AP5Z1	NR_157345.1	n.681C>T		non_coding_transcript_exon_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.588C>T	p.Ser196=	synonymous_variant	5/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152228 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00140 AC: 216 AN: 154698 Hom.: 3 AF XY: 0.00132 AC XY: 109 AN XY: 82440

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000665

Gnomad OTH exome AF: 0.000915

GnomAD4 exome AF: 0.000408 AC: 570 AN: 1398136 Hom.: 6 Cov.: 32 AF XY: 0.000396 AC XY: 273 AN XY: 689740

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.0000279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0117

Gnomad4 SAS exome AF: 0.000669

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.000896

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74500

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.00953 AC: 33 AN: 3478

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	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.017
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146665638; hg19: chr7-4823396; COSMIC: COSV62241119; COSMIC: COSV62241119;