19-54143706-A-G

Position:

• chr19-54143706-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_014516.4(CNOT3):​c.215A>G​(p.Lys72Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNOT3. . Trascript score misZ 3.772 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder with speech delay, autism, and dysmorphic facies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.215A>G	p.Lys72Arg	missense_variant	5/18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.215A>G	p.Lys72Arg	missense_variant	5/18	1	NM_014516.4	ENSP00000221232	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;.;.;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Uncertain	0.083	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;.;.;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.74
MutPred		0.68		Loss of methylation at K72 (P = 0.018);Loss of methylation at K72 (P = 0.018);Loss of methylation at K72 (P = 0.018);Loss of methylation at K72 (P = 0.018);Loss of methylation at K72 (P = 0.018);
MVP		0.82
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr19-54647442;