rs184752711

chr7-4789827-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014855.3(AP5Z1):c.1708-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,551,156 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 32)
  • Exomes 𝑓: 0.014 (211 hom.)
• Consequence: AP5Z1 NM_014855.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004138
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.434

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-4789827-C-T is Benign according to our data. Variant chr7-4789827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 360335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4789827-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0097 (1476/152190) while in subpopulation NFE AF= 0.0166 (1125/67976). AF 95% confidence interval is 0.0157. There are 12 homozygotes in gnomad4. There are 650 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.1708-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649063.2
AP5Z1	NM_001364858.1	c.1240-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AP5Z1	XM_047421098.1	c.1372-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AP5Z1	NR_157345.1	n.1839-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1708-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1477 AN: 152070 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.0104 AC: 1601 AN: 154540 Hom.: 11 AF XY: 0.0111 AC XY: 917 AN XY: 82302

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00413

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0145 AC: 20284 AN: 1398966 Hom.: 211 Cov.: 31 AF XY: 0.0144 AC XY: 9962 AN XY: 690244

Gnomad4 AFR exome AF: 0.00199

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.00726

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00970 AC: 1476 AN: 152190 Hom.: 12 Cov.: 32 AF XY: 0.00874 AC XY: 650 AN XY: 74382

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.00603

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0137 Hom.: 9

Bravo AF: 0.00865

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 20, 2020

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 04, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.4
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs184752711; hg19: chr7-4829458;