NM_014516.4:c.1440dupT

Variant names:

• chr19-54149592-C-CT
• rs1555806893
• NM_014516.4:c.1440dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014516.4(CNOT3):​c.1440dupT​(p.Gly481TrpfsTer34) variant causes a frameshift change involving the alteration of a non-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: -0.144
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with speech delay, autism, and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

LOC102724273 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 19-54149592-C-CT is Pathogenic according to our data. Variant chr19-54149592-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 522097.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT3	NM_014516.4	MANE Select	c.1440dupT	p.Gly481TrpfsTer34	frameshift	Exon 13 of 18	NP_055331.1	O75175
	CNOT3	NM_001440653.1		c.1443dupT	p.Gly482TrpfsTer34	frameshift	Exon 13 of 18	NP_001427582.1
	CNOT3	NM_001440654.1		c.1440dupT	p.Gly481TrpfsTer34	frameshift	Exon 13 of 18	NP_001427583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT3	ENST00000221232.11	TSL:1 MANE Select	c.1440dupT	p.Gly481TrpfsTer34	frameshift	Exon 13 of 18	ENSP00000221232.5	O75175
	CNOT3	ENST00000358389.7	TSL:1	c.1440dupT	p.Gly481TrpfsTer34	frameshift	Exon 12 of 17	ENSP00000351159.4	O75175
	CNOT3	ENST00000896564.1		c.1443dupT	p.Gly482TrpfsTer34	frameshift	Exon 13 of 18	ENSP00000566623.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555806893; hg19: chr19-54653327;