dbSNP rs2075353663: CNOT3:p.Arg750Gln (chr19-54155394-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_014516.4(CNOT3):c.2249G>A(p.Arg750Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R750P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CNOT3
NM_014516.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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 3 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.40871418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4 link	c.2249G>A	p.Arg750Gln	missense_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1	O75175A0A024R4R3
LENG1	NM_024316.3 link	c.*327C>T		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>A	p.Arg750Gln	missense_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5		O75175
LENG1	ENST00000222224.4 link	c.*327C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3		Q96BZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721118

show subpopulations

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:

0.00000181

AC:

AN:

1102514

Other (OTH)

AF:

0.00

AC:

AN:

59924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.038

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

9.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.3

N;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.010

D;.;T

Sift4G

Benign

0.094

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.58

MutPred

0.25

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;

MVP

0.60

ClinPred

0.94

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.80

Mutation Taster

=70/30

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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rs2075353663

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over