Genetic Variant CNOT10:p.Ile515Leu (chr3-32737438-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015442.3(CNOT10):c.1543A>C(p.Ile515Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,611,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CNOT10
NM_015442.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

Variant links:

Genes affected

CNOT10 (HGNC:23817): (CCR4-NOT transcription complex subunit 10) Predicted to be involved in mRNA catabolic process and negative regulation of translation. Located in membrane. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT10 links:

CNOT10-AS1 (HGNC:41031): (CNOT10 antisense RNA 1)

CNOT10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.079681635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT10	NM_015442.3 link	c.1543A>C	p.Ile515Leu	missense_variant	Exon 13 of 19	ENST00000328834.10	NP_056257.1	Q9H9A5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT10	ENST00000328834.10 link	c.1543A>C	p.Ile515Leu	missense_variant	Exon 13 of 19	1	NM_015442.3	ENSP00000330060.5		Q9H9A5-1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152236

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250914

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

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:

0.000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

205

AN:

1459676

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

726346

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.000176

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000737

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1543A>C (p.I515L) alteration is located in exon 13 (coding exon 13) of the CNOT10 gene. This alteration results from a A to C substitution at nucleotide position 1543, causing the isoleucine (I) at amino acid position 515 to be replaced by a leucine (L). 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

0.065

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.011

T;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.0048

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0056

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

L;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.59

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.22

MVP

0.10

MPC

0.26

ClinPred

0.11

GERP RS

5.5

Varity_R

0.11

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

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