4-25391010-T-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.700T>A(p.Phe234Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,606,254 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ANAPC4 NM_013367.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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=0.18095452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANAPC4	NM_013367.3	c.700T>A	p.Phe234Ile	missense_variant	9/29	ENST00000315368.8
ANAPC4	NM_001286756.2	c.700T>A	p.Phe234Ile	missense_variant	9/29
ANAPC4	XM_011513838.2	c.364T>A	p.Phe122Ile	missense_variant	7/27
ANAPC4	XM_047450152.1	c.700T>A	p.Phe234Ile	missense_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANAPC4	ENST00000315368.8	c.700T>A	p.Phe234Ile	missense_variant	9/29	1	NM_013367.3	P4
ANAPC4	ENST00000510092.5	c.700T>A	p.Phe234Ile	missense_variant	9/29	5		A1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.00191

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

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: 0.0000131 AC: 19 AN: 1454004 Hom.: 0 Cov.: 28 AF XY: 0.00000829 AC XY: 6 AN XY: 723918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 9.05e-7

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74394

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00131

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: 0.00191

Bravo AF: 0.000389

ExAC AF: 0.00000824 AC: 1

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

Apr 11, 2023

The c.700T>A (p.F234I) alteration is located in exon 9 (coding exon 8) of the ANAPC4 gene. This alteration results from a T to A substitution at nucleotide position 700, causing the phenylalanine (F) at amino acid position 234 to be replaced by an isoleucine (I). 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	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.090
Sift	Benign	0.45	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0060	B;.
Vest4		0.53
MutPred		0.38		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);
MVP		0.59
MPC		0.72
ClinPred		0.32	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.44

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: rs773529954; hg19: chr4-25392632;