19-54143660-C-G

Position:

• chr19-54143660-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_014516.4(CNOT3):​c.169C>G​(p.Arg57Gly) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT3 NM_014516.4 missense, splice_region
• Scores: Splicing: ADA: 0.9752
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.66

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]

CNOT3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNOT3. . Trascript score misZ 3.772 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder with speech delay, autism, and dysmorphic facies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 19-54143660-C-G is Pathogenic according to our data. Variant chr19-54143660-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2629348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.169C>G	p.Arg57Gly	missense_variant, splice_region_variant	5/18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.169C>G	p.Arg57Gly	missense_variant, splice_region_variant	5/18	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CNOT3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2022

The CNOT3 c.169C>G variant is predicted to result in the amino acid substitution p.Arg57Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant was documented to have occurred de novo in an individual with CNOT3-related disorder at PreventionGenetics (internal data). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.5	D;.;.;.;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.85
MutPred		0.74		Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);
MVP		0.76
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54647396;