Genetic Variant CNOT3:p.Arg750Pro (chr19-54155394-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_014516.4(CNOT3):c.2249G>C(p.Arg750Pro) 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNOT3
NM_014516.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.20

Publications

0 publications found

Variant links:

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 links:

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

LENG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4 link	c.2249G>C	p.Arg750Pro	missense_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1	O75175A0A024R4R3
LENG1	NM_024316.3 link	c.*327C>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2	Q96BZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11 link	c.2249G>C	p.Arg750Pro	missense_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5		O75175
LENG1	ENST00000222224.4 link	c.*327C>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3		Q96BZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1449110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721114

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.00

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

85282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102508

Other (OTH)

AF:

0.00

AC:

AN:

59924

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2249G>C (p.R750P) alteration is located in exon 18 (coding exon 17) of the CNOT3 gene. This alteration results from a G to C substitution at nucleotide position 2249, causing the arginine (R) at amino acid position 750 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

9.2

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.4

D;.;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.73

MutPred

0.33

Gain of loop (P = 0.024);Gain of loop (P = 0.024);.;

MVP

0.51

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.95

Mutation Taster

=51/49

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over