rs11866002

chr16-58553833-C-Gchr16-58553833-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Interaction with ZFP36 (size 215) in uniprot entity CNOT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_016284.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNOT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNOT1	NM_016284.5	c.2919G>C	p.Gln973His	missense_variant	22/49	ENST00000317147.10
CNOT1	NM_001265612.2	c.2904G>C	p.Gln968His	missense_variant	22/49
CNOT1	NM_206999.3	c.2919G>C	p.Gln973His	missense_variant	22/31
CNOT1	NR_049763.2	n.3177G>C		non_coding_transcript_exon_variant	22/50

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT1	ENST00000317147.10	c.2919G>C	p.Gln973His	missense_variant	22/49	1	NM_016284.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	6.5e-8	P;P;P
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.068	T;T;D
Polyphen		0.98	D;D;D
Vest4		0.69
MutPred		0.30		Gain of catalytic residue at L975 (P = 0.1308);.;Gain of catalytic residue at L975 (P = 0.1308);
MVP		0.47
MPC		2.2
ClinPred		0.91	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.56

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

Other links and lift over

dbSNP: rs11866002; hg19: chr16-58587737;