19-54143003-G-C

Variant names:

• chr19-54143003-G-C
• NM_014516.4:c.25G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_014516.4(CNOT3):​c.25G>C​(p.Gly9Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to 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: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.11

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-54143003-G-C is Pathogenic according to our data. Variant chr19-54143003-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3387804.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.25G>C	p.Gly9Arg	missense_variant, splice_region_variant	Exon 2 of 18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.25G>C	p.Gly9Arg	missense_variant, splice_region_variant	Exon 2 of 18	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with speech delay, autism, and dysmorphic facies Pathogenic:1

Aug 13, 2023

Cytogenetique et Genetique Moleculaire, CHU Besancon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_014516.4:c.25G>C variant is a missense variant in a gene with low rate of benign missense mutations and for which missense mutation is a common mechanism of a disease (Missense Z-score =3,78 ; https://gnomad.broadinstitute.org/) (PP2). This variant is predicted to result in a alteration of consensus splice site (Spip and Splice AI)(PP3). This variant was found in a proband with developmental delay and dysmorphic features. The variant has been identified as a de novo occurrence, without confirmation of paternity and maternity, in one individual with a phenotype consistent with the gene (PM6). This variant is not present in gnomAD v4.1.0 (PM2; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for CNOT3-related neurodevelopmental disorders based on the ACMG/AMP criteria applied (PM2 PM6 PP2 PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.;.;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.7	D;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;.;.;.
Sift4G	Uncertain	0.031	D;.;.;.;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.65
MutPred		0.47		Loss of ubiquitination at K4 (P = 0.0134);Loss of ubiquitination at K4 (P = 0.0134);Loss of ubiquitination at K4 (P = 0.0134);Loss of ubiquitination at K4 (P = 0.0134);Loss of ubiquitination at K4 (P = 0.0134);
MVP		0.40
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.83
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

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: chr19-54646739;