Genetic Variant CNOT1:p.Gln973His (chr16-58553833-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_016284.5(CNOT1):c.2919G>C(p.Gln973His) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q973Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CNOT1
NM_016284.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.76

Publications

41 publications found

Variant links:

Genes affected

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CNOT1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
holoprosencephaly 12 with or without pancreatic agenesis
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
Vissers-Bodmer syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

CNOT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016284.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNOT1	NM_016284.5	MANE Select	c.2919G>C	p.Gln973His	missense	Exon 22 of 49	NP_057368.3
CNOT1	NM_001265612.2		c.2904G>C	p.Gln968His	missense	Exon 22 of 49	NP_001252541.1
CNOT1	NM_206999.3		c.2919G>C	p.Gln973His	missense	Exon 22 of 31	NP_996882.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.2919G>C	p.Gln973His	missense	Exon 22 of 49	ENSP00000320949.5
CNOT1	ENST00000569240.5	TSL:1	c.2904G>C	p.Gln968His	missense	Exon 22 of 49	ENSP00000455635.1
CNOT1	ENST00000441024.6	TSL:1	c.2919G>C	p.Gln973His	missense	Exon 22 of 31	ENSP00000413113.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.13

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.5

PhyloP100

1.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Uncertain

0.0080

Sift4G

Benign

0.068

Polyphen

0.98

Vest4

0.69

MutPred

0.30

Gain of catalytic residue at L975 (P = 0.1308)

MVP

0.47

MPC

2.2

ClinPred

0.91

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.56

Mutation Taster

=31/69

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over