Genetic Variant CNOT4:p.Val548Ile (chr7-135364052-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001190850.2(CNOT4):c.1642G>A(p.Val548Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,593,110 control chromosomes in the GnomAD database, including 51,994 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4652 hom., cov: 31)

Exomes 𝑓: 0.25 ( 47342 hom. )

Consequence

CNOT4
NM_001190850.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

Publications

26 publications found

Variant links:

Genes affected

CNOT4 (HGNC:7880): (CCR4-NOT transcription complex subunit 4) The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

CNOT4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.902384E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT4	NM_001190850.2 link	c.1642G>A	p.Val548Ile	missense_variant	Exon 11 of 12	ENST00000541284.6	NP_001177779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT4	ENST00000541284.6 link	c.1642G>A	p.Val548Ile	missense_variant	Exon 11 of 12	5	NM_001190850.2	ENSP00000445508.1		O95628-10

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36166

AN:

151602

Hom.:

4650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.287

Gnomad ASJ

AF:

0.235

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.234

GnomAD2 exomes

AF:

0.270

AC:

61690

AN:

228346

AF XY:

0.261

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.524

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.249

AC:

358926

AN:

1441390

Hom.:

47342

Cov.:

AF XY:

0.246

AC XY:

176320

AN XY:

717494

show subpopulations

African (AFR)

AF:

0.184

AC:

6144

AN:

33376

American (AMR)

AF:

0.350

AC:

15592

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6035

AN:

26068

East Asian (EAS)

AF:

0.500

AC:

19823

AN:

39650

South Asian (SAS)

AF:

0.181

AC:

15552

AN:

85930

European-Finnish (FIN)

AF:

0.248

AC:

9427

AN:

38008

Middle Eastern (MID)

AF:

0.155

AC:

889

AN:

5752

European-Non Finnish (NFE)

AF:

0.244

AC:

270505

AN:

1107928

Other (OTH)

AF:

0.249

AC:

14959

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11634

23269

34903

46538

58172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9326

18652

27978

37304

46630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.239

AC:

36201

AN:

151720

Hom.:

4652

Cov.:

AF XY:

0.239

AC XY:

17739

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.184

AC:

7604

AN:

41350

American (AMR)

AF:

0.287

AC:

4372

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.235

AC:

814

AN:

3468

East Asian (EAS)

AF:

0.519

AC:

2674

AN:

5152

South Asian (SAS)

AF:

0.176

AC:

839

AN:

4778

European-Finnish (FIN)

AF:

0.238

AC:

2493

AN:

10488

Middle Eastern (MID)

AF:

0.151

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.245

AC:

16648

AN:

67918

Other (OTH)

AF:

0.240

AC:

506

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1343

2686

4028

5371

6714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.250

Hom.:

17229

Bravo

AF:

0.243

TwinsUK

AF:

0.239

AC:

888

ALSPAC

AF:

0.248

AC:

955

ESP6500AA

AF:

0.201

AC:

352

ESP6500EA

AF:

0.250

AC:

996

ExAC

AF:

0.263

AC:

30036

Asia WGS

AF:

0.343

AC:

1190

AN:

3478

EpiCase

AF:

0.231

EpiControl

AF:

0.225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.76

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.00079

T;T

MetaSVM

Benign

-0.93

PhyloP100

2.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.14

Sift

Benign

0.78

T;T

Sift4G

Benign

0.64

T;T

Vest4

0.062

MPC

0.39

ClinPred

0.0078

GERP RS

5.0

gMVP

0.16

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over