rs1057519956

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_005444.3(CNOT9):​c.259T>C​(p.Ser87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S87C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CNOT9
NM_005444.3 missense

Scores

10
5
3

Clinical Significance

Likely pathogenic no assertion criteria provided P:5

Conservation

PhyloP100: 8.02
Variant links:
Genes affected
CNOT9 (HGNC:10445): (CCR4-NOT transcription complex subunit 9) This gene encodes a member of the highly conserved RCD1 protein family. The encoded protein is a transcriptional cofactor and a core protein of the CCR4-NOT complex. It may be involved in signal transduction as well as retinoic acid-regulated cell differentiation and development. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a chain CCR4-NOT transcription complex subunit 9 (size 298) in uniprot entity CNOT9_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_005444.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-218583026-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376527.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889
PP5
Variant 2-218583025-T-C is Pathogenic according to our data. Variant chr2-218583025-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376526.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNOT9NM_005444.3 linkuse as main transcriptc.259T>C p.Ser87Pro missense_variant 3/8 ENST00000273064.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNOT9ENST00000273064.11 linkuse as main transcriptc.259T>C p.Ser87Pro missense_variant 3/81 NM_005444.3 P1Q92600-1
CNOT9ENST00000295701.9 linkuse as main transcriptc.259T>C p.Ser87Pro missense_variant 3/81 Q92600-3
CNOT9ENST00000627282.2 linkuse as main transcriptc.259T>C p.Ser87Pro missense_variant 3/92 Q92600-2
CNOT9ENST00000432877.5 linkuse as main transcriptc.*151T>C 3_prime_UTR_variant, NMD_transcript_variant 4/53

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
.;T;T;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;.;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Uncertain
0.056
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-4.6
.;D;D;D
REVEL
Pathogenic
0.74
Sift
Benign
0.034
.;D;D;D
Sift4G
Uncertain
0.020
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.89
MutPred
0.75
Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);Loss of glycosylation at S87 (P = 0.0588);
MVP
0.73
MPC
2.6
ClinPred
0.99
D
GERP RS
6.1
Varity_R
0.96
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1057519956; hg19: chr2-219447748; COSMIC: COSV55299564; COSMIC: COSV55299564; API