chr19-54143003-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9D) has been classified as Uncertain significance.

• 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
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 3387804.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.25G>C	p.Gly9Arg	missense splice_region	Exon 2 of 18	NP_055331.1	O75175
	CNOT3	NM_001440653.1		c.25G>C	p.Gly9Arg	missense splice_region	Exon 2 of 18	NP_001427582.1
	CNOT3	NM_001440654.1		c.25G>C	p.Gly9Arg	missense splice_region	Exon 2 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.25G>C	p.Gly9Arg	missense splice_region	Exon 2 of 18	ENSP00000221232.5	O75175
	CNOT3	ENST00000358389.7	TSL:1	c.25G>C	p.Gly9Arg	missense splice_region	Exon 1 of 17	ENSP00000351159.4	O75175
	CNOT3	ENST00000896564.1		c.25G>C	p.Gly9Arg	missense splice_region	Exon 2 of 18	ENSP00000566623.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.47		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
Mutation Taster		=18/82	disease causing

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

Other links and lift over

hg19: chr19-54646739;