rs184752711

Positions:

chr7-4789827-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014855.3(AP5Z1):c.1708-5C>T variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00004138

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.434

Variant links:

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]

AP5Z1 links:

AP5Z1 (HGNC:):

AP5Z1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
AP5Z1	NM_014855.3 linkuse as main transcript	c.1708-5C>T	splice_region_variant, intron_variant	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 linkuse as main transcript	c.1240-5C>T	splice_region_variant, intron_variant		NP_001351787.1
AP5Z1	XM_047421098.1 linkuse as main transcript	c.1372-5C>T	splice_region_variant, intron_variant		XP_047277054.1
AP5Z1	NR_157345.1 linkuse as main transcript	n.1839-5C>T	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 linkuse as main transcript	c.1708-5C>T		splice_region_variant, intron_variant			NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.00971

AC:

1477

AN:

152070

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0111

AC XY:

917

AN XY:

82302

show subpopulations

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.:

AF XY:

0.0144

AC XY:

9962

AN XY:

690244

show subpopulations

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.:

Cov.:

AF XY:

0.00874

AC XY:

650

AN XY:

74382

show subpopulations

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.:

Bravo

AF:

0.00865

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 29, 2024

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over