rs73305392

Variant names:

• chr7-4790664-C-T
• rs73305392
• NM_014855.3:c.1939-9C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014855.3(AP5Z1):​c.1939-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,611,958 control chromosomes in the GnomAD database, including 778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (383 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (395 hom.)
• Consequence: AP5Z1 NM_014855.3 intron
• Scores: Splicing: ADA: 0.000001825
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.467

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=-0.61).
• BP6: Variant 7-4790664-C-T is Benign according to our data. Variant chr7-4790664-C-T is described in ClinVar as [Benign]. Clinvar id is 360341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1939-9C>T		intron_variant	Intron 15 of 16	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1471-9C>T		intron_variant	Intron 14 of 15		NP_001351787.1
AP5Z1	XM_047421098.1	c.1603-9C>T		intron_variant	Intron 13 of 14		XP_047277054.1
AP5Z1	NR_157345.1	n.2070-9C>T		intron_variant	Intron 15 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1939-9C>T		intron_variant	Intron 15 of 16		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6316 AN: 152132 Hom.: 383 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0129 AC: 3169 AN: 245626 Hom.: 159 AF XY: 0.0105 AC XY: 1405 AN XY: 133922

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.00323

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000618

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.00873

GnomAD4 exome AF: 0.00929 AC: 13561 AN: 1459708 Hom.: 395 Cov.: 32 AF XY: 0.00849 AC XY: 6163 AN XY: 726118

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.00852

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00660

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0415 AC: 6325 AN: 152250 Hom.: 383 Cov.: 33 AF XY: 0.0400 AC XY: 2976 AN XY: 74460

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00625

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0220 Hom.: 65

Bravo AF: 0.0468

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00636

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 01, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000018
dbscSNV1_RF	Benign	0.028
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: rs73305392; hg19: chr7-4830295;