19-54155378-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_014516.4(CNOT3):​c.2233C>T​(p.Arg745Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CNOT3
NM_014516.4 missense

Scores

5
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52
Variant links:
Genes affected
CNOT3 (HGNC:7879): (CCR4-NOT transcription complex subunit 3) Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]
LENG1 (HGNC:15502): (leukocyte receptor cluster member 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_014516.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CNOT3NM_014516.4 linkc.2233C>T p.Arg745Cys missense_variant Exon 18 of 18 ENST00000221232.11 NP_055331.1 O75175A0A024R4R3
LENG1NM_024316.3 linkc.*343G>A 3_prime_UTR_variant Exon 4 of 4 ENST00000222224.4 NP_077292.2 Q96BZ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CNOT3ENST00000221232.11 linkc.2233C>T p.Arg745Cys missense_variant Exon 18 of 18 1 NM_014516.4 ENSP00000221232.5 O75175
LENG1ENST00000222224 linkc.*343G>A 3_prime_UTR_variant Exon 4 of 4 1 NM_024316.3 ENSP00000222224.3 Q96BZ8

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 24, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Benign
0.0088
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
T;T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Benign
0.080
D
MetaRNN
Uncertain
0.59
D;D;D
MetaSVM
Benign
-0.66
T
MutationAssessor
Uncertain
2.0
M;M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D;.;D
REVEL
Benign
0.26
Sift
Uncertain
0.0010
D;.;T
Sift4G
Pathogenic
0.0
D;D;T
Polyphen
1.0
D;D;.
Vest4
0.47
MutPred
0.54
Loss of disorder (P = 0.0393);Loss of disorder (P = 0.0393);.;
MVP
0.38
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.69
gMVP
0.66

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

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

Other links and lift over

dbSNP: rs1451115570; hg19: chr19-54659116; API