Variant 12-121327103-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_016237.5(ANAPC5):c.1433C>T(p.Ala478Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,602,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ANAPC5
NM_016237.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.02

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANAPC5	NM_016237.5 link	c.1433C>T	p.Ala478Val	missense_variant	11/17	ENST00000261819.8	NP_057321.2	Q9UJX4-1
ANAPC5	NM_001330489.2 link	c.1394C>T	p.Ala465Val	missense_variant	11/17		NP_001317418.1	Q9UJX4F5H0F9
ANAPC5	NM_001137559.1 link	c.1097C>T	p.Ala366Val	missense_variant	11/17		NP_001131031.1	Q9UJX4-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANAPC5	ENST00000261819.8 link	c.1433C>T	p.Ala478Val	missense_variant	11/17	1	NM_016237.5	ENSP00000261819.3		Q9UJX4-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131962

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000483

AC:

AN:

1450538

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

AN XY:

721106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

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

Oct 05, 2023

The c.1433C>T (p.A478V) alteration is located in exon 11 (coding exon 11) of the ANAPC5 gene. This alteration results from a C to T substitution at nucleotide position 1433, causing the alanine (A) at amino acid position 478 to be replaced by a valine (V). 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

0.27

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.034

.;T;T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.7

.;.;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.74

T;T;T;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;D;D

Vest4

0.93

MutPred

0.57

.;.;Gain of catalytic residue at A478 (P = 0.0022);.;

MVP

0.75

MPC

1.6

ClinPred

0.42

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.67

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