NM_014516.4:c.26G>A

Variant names:

• chr19-54143119-G-A
• NM_014516.4:c.26G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_014516.4(CNOT3):​c.26G>A​(p.Gly9Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT3 NM_014516.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.26G>A	p.Gly9Asp	missense_variant, splice_region_variant	Exon 3 of 18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.26G>A	p.Gly9Asp	missense_variant, splice_region_variant	Exon 3 of 18	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;.
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PhyloP100		9.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;.;.;.
Sift4G	Uncertain	0.013	D;.;.;.;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.60
MutPred		0.51		Gain of ubiquitination at K6 (P = 0.0239);Gain of ubiquitination at K6 (P = 0.0239);Gain of ubiquitination at K6 (P = 0.0239);Gain of ubiquitination at K6 (P = 0.0239);Gain of ubiquitination at K6 (P = 0.0239);
MVP		0.44
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		0.53
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

hg19: chr19-54646855;