rs192794637

chr7-4791289-C-Achr7-4791289-C-Gchr7-4791289-C-T

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.2328C>A(p.Ser776Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,612,544 control chromosomes in the GnomAD database, including 4 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 0.0043 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.453

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=0.003862381).
• BP6: Variant 7-4791289-C-A is Benign according to our data. Variant chr7-4791289-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 585437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.2328C>A	p.Ser776Arg	missense_variant	17/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.1860C>A	p.Ser620Arg	missense_variant	16/16
AP5Z1	XM_047421098.1	c.1992C>A	p.Ser664Arg	missense_variant	15/15
AP5Z1	NR_157345.1	n.2459C>A		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.2328C>A	p.Ser776Arg	missense_variant	17/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 646 AN: 152266 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00112 AC: 277 AN: 246362 Hom.: 1 AF XY: 0.000900 AC XY: 121 AN XY: 134378

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000727

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000424 AC: 619 AN: 1460160 Hom.: 1 Cov.: 32 AF XY: 0.000388 AC XY: 282 AN XY: 726342

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152384 Hom.: 3 Cov.: 33 AF XY: 0.00386 AC XY: 288 AN XY: 74520

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000773 Hom.: 2

Bravo AF: 0.00480

ESP6500AA AF: 0.0135 AC: 58

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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 13, 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	Invitae	Jan 25, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.1
Dann	Benign	0.70
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.020
Sift	Benign	0.40	T;.
Sift4G	Benign	0.48	T;.
Polyphen		0.017	B;B
Vest4		0.096
MutPred		0.15		Gain of MoRF binding (P = 0.1253);Gain of MoRF binding (P = 0.1253);
MVP		0.014
ClinPred		0.0015	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.36

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: rs192794637; hg19: chr7-4830920;