12-121318392-C-T

Position:

chr12-121318392-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_016237.5(ANAPC5):c.1778G>A(p.Arg593Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,611,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ANAPC5
NM_016237.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Variant links:

Genes affected

ANAPC5 (HGNC:15713): (anaphase promoting complex subunit 5) This gene encodes a tetratricopeptide repeat-containing component of the anaphase promoting complex/cyclosome (APC/C), a large E3 ubiquitin ligase that controls cell cycle progression by targeting a number of cell cycle regulators such as B-type cyclins for 26S proteasome-mediated degradation through ubiquitination. The encoded protein is required for the proper ubiquitination function of APC/C and for the interaction of APC/C with transcription coactivators. It also interacts with polyA binding protein and represses internal ribosome entry site-mediated translation. Multiple transcript variants encoding different isoforms have been found for this gene. These differences cause translation initiation at a downstream AUG and result in a shorter protein (isoform b), compared to isoform a. [provided by RefSeq, Nov 2008]

ANAPC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANAPC5. . Gene score misZ 2.2973 (greater than the threshold 3.09). Trascript score misZ 3.2965 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia.

BP4

Computational evidence support a benign effect (MetaRNN=0.19000065).

BS2

High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ANAPC5	NM_016237.5 linkuse as main transcript	c.1778G>A	p.Arg593Gln	missense_variant	15/17	ENST00000261819.8	NP_057321.2
ANAPC5	NM_001330489.2 linkuse as main transcript	c.1739G>A	p.Arg580Gln	missense_variant	15/17		NP_001317418.1
ANAPC5	NM_001137559.1 linkuse as main transcript	c.1442G>A	p.Arg481Gln	missense_variant	15/17		NP_001131031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANAPC5	ENST00000261819.8 linkuse as main transcript	c.1778G>A	p.Arg593Gln	missense_variant	15/17	1	NM_016237.5	ENSP00000261819	P1	Q9UJX4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248688

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1459588

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726016

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The c.1778G>A (p.R593Q) alteration is located in exon 15 (coding exon 15) of the ANAPC5 gene. This alteration results from a G to A substitution at nucleotide position 1778, causing the arginine (R) at amino acid position 593 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0072

.;T;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.087

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.8

.;.;L;.

MutationTaster

Benign

0.95

D;D;D;D;D;D

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.23

N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.57

T;T;T;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.24, 0.36

.;.;B;B

Vest4

0.27

MutPred

0.42

.;.;Gain of catalytic residue at L590 (P = 0);.;

MVP

0.69

MPC

0.75

ClinPred

0.41

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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