19-54143732-C-A

Position:

• chr19-54143732-C-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_014516.4(CNOT3):​c.241C>A​(p.Arg81Ser) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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, 0.918
• PP5: Variant 19-54143732-C-A is Pathogenic according to our data. Variant chr19-54143732-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1713134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.241C>A	p.Arg81Ser	missense_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.241C>A	p.Arg81Ser	missense_variant	5/18	1	NM_014516.4	ENSP00000221232	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with speech delay, autism, and dysmorphic facies Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	This CNOT3 missense variant at c.241C>A (p.R81S) was seen on exome through the Texome project (R01HG011795). This variant is de novo in our patient (PS2). It has not been observed in gnomAD (PM2). This variant is predicted to be deleterious by multiple computational models (CADD: 31.000)(PP3), and the evolutionary conservation of this residue is high. We believe this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.93
MutPred		0.79		Gain of ubiquitination at K82 (P = 0.0358);Gain of ubiquitination at K82 (P = 0.0358);Gain of ubiquitination at K82 (P = 0.0358);Gain of ubiquitination at K82 (P = 0.0358);Gain of ubiquitination at K82 (P = 0.0358);
MVP		0.93
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54647468;