NM_014855.3:c.2379G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014855.3(AP5Z1):c.2379G>T(p.Thr793Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,609,480 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T793T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 33)

Exomes 𝑓: 0.021 ( 416 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.83

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 48
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AP5Z1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 7-4791340-G-T is Benign according to our data. Variant chr7-4791340-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.016 (2442/152370) while in subpopulation SAS AF = 0.0252 (122/4832). AF 95% confidence interval is 0.0226. There are 33 homozygotes in GnomAd4. There are 1157 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AP5Z1	NM_014855.3 link	c.2379G>T	p.Thr793Thr	synonymous_variant	Exon 17 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1 link	c.1911G>T	p.Thr637Thr	synonymous_variant	Exon 16 of 16		NP_001351787.1
AP5Z1	XM_047421098.1 link	c.2043G>T	p.Thr681Thr	synonymous_variant	Exon 15 of 15		XP_047277054.1
AP5Z1	NR_157345.1 link	n.2510G>T		non_coding_transcript_exon_variant	Exon 17 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.2379G>T	p.Thr793Thr	synonymous_variant	Exon 17 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2442

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0176

AC:

4178

AN:

237522

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00641

Gnomad NFE exome

AF:

0.0226

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0214

AC:

31118

AN:

1457110

Hom.:

416

Cov.:

AF XY:

0.0217

AC XY:

15690

AN XY:

724538

show subpopulations

African (AFR)

AF:

0.00371

AC:

124

AN:

33412

American (AMR)

AF:

0.0151

AC:

668

AN:

44328

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

845

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.0229

AC:

1958

AN:

85608

European-Finnish (FIN)

AF:

0.00681

AC:

353

AN:

51846

Middle Eastern (MID)

AF:

0.0490

AC:

281

AN:

5738

European-Non Finnish (NFE)

AF:

0.0229

AC:

25456

AN:

1110460

Other (OTH)

AF:

0.0238

AC:

1433

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2033

4066

6100

8133

10166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

964

1928

2892

3856

4820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2442

AN:

152370

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1157

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41602

American (AMR)

AF:

0.0178

AC:

273

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0252

AC:

122

AN:

4832

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0236

AC:

1604

AN:

68030

Other (OTH)

AF:

0.0236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0165

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Feb 20, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia 48

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 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 provided

Benign:2

Aug 30, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Hereditary spastic paraplegia

Benign:1

Oct 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.83

CADD

Benign

0.019

(source)

DANN

Benign

0.89

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over