4-145081748-A-C

Variant names:

• chr4-145081748-A-C
• rs749034185
• NM_001256706.2:c.118T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256706.2(ANAPC10):​c.118T>G​(p.Phe40Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANAPC10 NM_001256706.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.64
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256706.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANAPC10	NM_001256706.2	MANE Select	c.118T>G	p.Phe40Val	missense splice_region	Exon 3 of 5	NP_001243635.1	Q9UM13
	ANAPC10	NM_001318367.2		c.220T>G	p.Phe74Val	missense splice_region	Exon 3 of 5	NP_001305296.1
	ANAPC10	NM_001256709.2		c.151T>G	p.Phe51Val	missense splice_region	Exon 5 of 7	NP_001243638.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANAPC10	ENST00000507656.6	TSL:1 MANE Select	c.118T>G	p.Phe40Val	missense splice_region	Exon 3 of 5	ENSP00000423995.1	Q9UM13
	ANAPC10	ENST00000309439.9	TSL:1	c.118T>G	p.Phe40Val	missense splice_region	Exon 3 of 5	ENSP00000310071.5	Q9UM13
	ANAPC10	ENST00000451299.6	TSL:1	c.118T>G	p.Phe40Val	missense splice_region	Exon 4 of 6	ENSP00000403891.2	Q9UM13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248816 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458496 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725512

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60262

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.53
Sift	Benign	0.065	T
Sift4G	Benign	0.48	T
Polyphen		0.99	D
Vest4		0.85
MutPred		0.63		Gain of ubiquitination at K37 (P = 0.0798)
MVP		0.84
MPC		1.2
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.61
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749034185; hg19: chr4-146002900;