Variant 2-111782370-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_022662.4(ANAPC1):c.5201A>G(p.Lys1734Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000682 in 1,613,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ANAPC1
NM_022662.4 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.98

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANAPC1	NM_022662.4 linkuse as main transcript	c.5201A>G	p.Lys1734Arg	missense_variant, splice_region_variant	43/48	ENST00000341068.8	NP_073153.1	Q9H1A4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ANAPC1	ENST00000341068.8 linkuse as main transcript	c.5201A>G	p.Lys1734Arg	missense_variant, splice_region_variant	43/48	1	NM_022662.4	ENSP00000339109.3	Q9H1A4
ANAPC1	ENST00000427997.5 linkuse as main transcript	c.3803A>G	p.Lys1268Arg	missense_variant, splice_region_variant	32/37	1		ENSP00000396695.1	H0Y564
ANAPC1	ENST00000643447.1 linkuse as main transcript	n.227A>G		splice_region_variant, non_coding_transcript_exon_variant	3/12			ENSP00000494863.1	A0A2R8YF63

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

246918

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

134114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000328

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:

0.00000616

AC:

AN:

1461162

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.5201A>G (p.K1734R) alteration is located in exon 43 (coding exon 42) of the ANAPC1 gene. This alteration results from a A to G substitution at nucleotide position 5201, causing the lysine (K) at amino acid position 1734 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.0067

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0079

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.68

REVEL

Benign

0.19

Sift

Benign

0.72

Sift4G

Benign

0.84

Polyphen

1.0

Vest4

0.49

MVP

0.65

ClinPred

0.42

GERP RS

4.2

Varity_R

0.14

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over