4-25390990-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013367.3(ANAPC4):c.680G>A(p.Gly227Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANAPC4 NM_013367.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

ANAPC4 (HGNC:19990): (anaphase promoting complex subunit 4) A large protein complex, termed the anaphase-promoting complex (APC), or the cyclosome, promotes metaphase-anaphase transition by ubiquitinating its specific substrates such as mitotic cyclins and anaphase inhibitor, which are subsequently degraded by the 26S proteasome. Biochemical studies have shown that the vertebrate APC contains eight subunits. The composition of the APC is highly conserved in organisms from yeast to humans. The exact function of this gene product is not known. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078689605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANAPC4	NM_013367.3	c.680G>A	p.Gly227Asp	missense_variant	9/29	ENST00000315368.8
ANAPC4	NM_001286756.2	c.680G>A	p.Gly227Asp	missense_variant	9/29
ANAPC4	XM_011513838.2	c.344G>A	p.Gly115Asp	missense_variant	7/27
ANAPC4	XM_047450152.1	c.680G>A	p.Gly227Asp	missense_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANAPC4	ENST00000315368.8	c.680G>A	p.Gly227Asp	missense_variant	9/29	1	NM_013367.3	P4
ANAPC4	ENST00000510092.5	c.680G>A	p.Gly227Asp	missense_variant	9/29	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.680G>A (p.G227D) alteration is located in exon 9 (coding exon 8) of the ANAPC4 gene. This alteration results from a G to A substitution at nucleotide position 680, causing the glycine (G) at amino acid position 227 to be replaced by an aspartic acid (D). 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	0.089
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0088	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.92	N;N
REVEL	Benign	0.080
Sift	Benign	0.52	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0010	B;.
Vest4		0.066
MutPred		0.33		Loss of glycosylation at S224 (P = 0.0692);Loss of glycosylation at S224 (P = 0.0692);
MVP		0.56
MPC		0.66
ClinPred		0.23	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-25392612;