rs2146822960

Variant names:

• chr19-54155349-G-A
• rs2146822960
• NM_014516.4:c.2204G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_014516.4(CNOT3):​c.2204G>A​(p.Arg735Gln) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R735L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20
• 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]

LENG1 (HGNC:15502): (leukocyte receptor cluster member 1)

ACMG classification

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

• PM1: In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_014516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-54155349-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3387818.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.2204G>A	p.Arg735Gln	missense_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1
LENG1	NM_024316.3	c.*372C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.2204G>A	p.Arg735Gln	missense_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
LENG1	ENST00000222224.4	c.*372C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 18, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.0	M;M;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.95	P;P;.
Vest4		0.63
MutPred		0.58		Gain of ubiquitination at K737 (P = 0.068);Gain of ubiquitination at K737 (P = 0.068);.;
MVP		0.71
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.76
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2146822960; hg19: chr19-54659087; COSMIC: COSV55359884; COSMIC: COSV55359884;