chr4-144995386-C-T

Variant names:

• chr4-144995386-C-T
• rs1731459048
• NM_001256706.2:c.545G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256706.2(ANAPC10):​c.545G>A​(p.Arg182His) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,454,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ANAPC10 NM_001256706.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

ANAPC10 (HGNC:24077): (anaphase promoting complex subunit 10) ANAPC10 is a core subunit of the anaphase-promoting complex (APC), or cyclosome, a ubiquitin protein ligase that is essential for progression through the cell cycle. APC initiates sister chromatid separation by ubiquitinating the anaphase inhibitor securin (PTTG1; MIM 604147) and triggers exit from mitosis by ubiquitinating cyclin B (CCNB1; MIM 123836), the activating subunit of cyclin-dependent kinase-1 (CDK1; MIM 116940) (summary by Wendt et al., 2001 [PubMed 11524682]).[supplied by OMIM, Feb 2011]

ENSG00000285713 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37518466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANAPC10	NM_001256706.2	c.545G>A	p.Arg182His	missense_variant	Exon 5 of 5	ENST00000507656.6	NP_001243635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANAPC10	ENST00000507656.6	c.545G>A	p.Arg182His	missense_variant	Exon 5 of 5	1	NM_001256706.2	ENSP00000423995.1
ENSG00000285713	ENST00000649263.1	n.327+69186G>A		intron_variant	Intron 4 of 8			ENSP00000497507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454990 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 724238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.545G>A (p.R182H) alteration is located in exon 5 (coding exon 4) of the ANAPC10 gene. This alteration results from a G to A substitution at nucleotide position 545, causing the arginine (R) at amino acid position 182 to be replaced by a histidine (H). 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	0.22
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T;T;T
Eigen	Benign	0.084
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;.;.;.
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.46	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.76	.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.17	.;T;T;T
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		0.0010	B;B;B;B
Vest4		0.48
MutPred		0.63		Loss of MoRF binding (P = 4e-04);Loss of MoRF binding (P = 4e-04);Loss of MoRF binding (P = 4e-04);Loss of MoRF binding (P = 4e-04);
MVP		0.82
MPC		0.40
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.53

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

Other links and lift over

dbSNP: rs1731459048; hg19: chr4-145916538; COSMIC: COSV58739104; COSMIC: COSV58739104;