7-4781669-C-G

Position:

chr7-4781669-C-G

Variant summary

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

The NM_014855.3(AP5Z1):c.281C>G(p.Ser94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,602,760 control chromosomes in the GnomAD database, including 454 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 0.016 ( 32 hom., cov: 33)

Exomes 𝑓: 0.021 ( 422 hom. )

Consequence

AP5Z1
NM_014855.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

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:

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 (MetaRNN=0.0061022043).

BP6

Variant 7-4781669-C-G is Benign according to our data. Variant chr7-4781669-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 128413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-4781669-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.016 (2437/152362) while in subpopulation SAS AF= 0.0252 (122/4834). AF 95% confidence interval is 0.0226. There are 32 homozygotes in gnomad4. There are 1153 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP5Z1	NM_014855.3 linkuse as main transcript	c.281C>G	p.Ser94Cys	missense_variant	3/17	ENST00000649063.2
AP5Z1	NM_001364858.1 linkuse as main transcript	c.-103+357C>G		intron_variant
AP5Z1	NR_157345.1 linkuse as main transcript	n.374C>G		non_coding_transcript_exon_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2 linkuse as main transcript	c.281C>G	p.Ser94Cys	missense_variant	3/17		NM_014855.3	P1	O43299-1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2439

AN:

152246

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:

0.0443

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0173

AC:

4250

AN:

245016

Hom.:

AF XY:

0.0180

AC XY:

2402

AN XY:

133572

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.00633

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0213

AC:

30874

AN:

1450398

Hom.:

422

Cov.:

AF XY:

0.0216

AC XY:

15531

AN XY:

719112

show subpopulations

Gnomad4 AFR exome

AF:

0.00375

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.0324

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0228

Gnomad4 FIN exome

AF:

0.00677

Gnomad4 NFE exome

AF:

0.0229

Gnomad4 OTH exome

AF:

0.0237

GnomAD4 genome

AF:

0.0160

AC:

2437

AN:

152362

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1153

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00428

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0252

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.0235

Gnomad4 OTH

AF:

0.0236

Alfa

AF:

0.0211

Hom.:

Bravo

AF:

0.0172

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00281

AC:

ESP6500EA

AF:

0.0245

AC:

208

ExAC

AF:

0.0171

AC:

2076

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0284

EpiControl

AF:

0.0272

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 23, 2019	- -

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 29, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

0.018

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.064

Sift

Benign

0.18

T;.

Sift4G

Benign

0.23

T;.

Polyphen

0.064

B;B

Vest4

0.19

ClinPred

0.015

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.23

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

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