NM_014516.4:c.1836_1837insATCA

Variant names:

• chr19-54152558-C-CATCA
• NM_014516.4:c.1836_1837insATCA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014516.4(CNOT3):​c.1836_1837insATCA​(p.Tyr613IlefsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT3 NM_014516.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.44

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54152558-C-CATCA is Pathogenic according to our data. Variant chr19-54152558-C-CATCA is described in ClinVar as [Pathogenic]. Clinvar id is 3387812.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.1836_1837insATCA	p.Tyr613IlefsTer19	frameshift_variant	Exon 15 of 18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.1836_1837insATCA	p.Tyr613IlefsTer19	frameshift_variant	Exon 15 of 18	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_014516.4:c.1836_1837insATCA variant is an frameshift variant in CNOT3 which is predicted to result in a premature stop codon, and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with developmental delay, strabismus and minor 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 (PM2; https://gnomad.broadinstitute.org/ v4.1.0). In summary, this variant meets criteria to be classified as pathogenic for CNOT3-related neurodevelopmental disorders based on the ACMG/AMP criteria applied (PVS1 PM2 PM6). -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr19-54656295;