2-111772465-A-T

Position:

• chr2-111772465-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022662.4(ANAPC1):​c.5595T>A​(p.Asp1865Glu) 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. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ANAPC1 NM_022662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.118

Genes affected

ANAPC1 (HGNC:19988): (anaphase promoting complex subunit 1) This gene encodes a subunit of the anaphase-promoting complex. This complex is an E3 ubiquitin ligase that regulates progression through the metaphase to anaphase portion of the cell cycle by ubiquitinating proteins which targets them for degradation. [provided by RefSeq, Dec 2011]

ANAPC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANAPC1. . Gene score misZ 0.98694 (greater than the threshold 3.09). Trascript score misZ 5.2521 (greater than threshold 3.09). GenCC has associacion of gene with Rothmund-Thomson syndrome type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14403516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANAPC1	NM_022662.4	c.5595T>A	p.Asp1865Glu	missense_variant	47/48	ENST00000341068.8	NP_073153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANAPC1	ENST00000341068.8	c.5595T>A	p.Asp1865Glu	missense_variant	47/48	1	NM_022662.4	ENSP00000339109.3
ANAPC1	ENST00000427997.5	c.4197T>A	p.Asp1399Glu	missense_variant	36/37	1		ENSP00000396695.1
ANAPC1	ENST00000462785.1	n.2289T>A		non_coding_transcript_exon_variant	3/4	2
ANAPC1	ENST00000643447.1	n.621T>A		non_coding_transcript_exon_variant	7/12			ENSP00000494863.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 23

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

Sep 11, 2024

The c.5595T>A (p.D1865E) alteration is located in exon 47 (coding exon 46) of the ANAPC1 gene. This alteration results from a T to A substitution at nucleotide position 5595, causing the aspartic acid (D) at amino acid position 1865 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.085
Sift	Benign	0.37	T
Sift4G	Benign	1.0	T
Polyphen		0.23	B
Vest4		0.60
MutPred		0.33		Loss of loop (P = 0.0374);
MVP		0.048
ClinPred		0.21	T
GERP RS		-0.89
Varity_R		0.042
gMVP		0.18

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: chr2-112530042;