16-58543411-GAAAAAA-GAAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_ModerateBP6BS2

The ENST00000441024.6(CNOT1):c.4628_4629delTT(p.Phe1543SerfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.000658 in 1,346,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

CNOT1
ENST00000441024.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.77

Publications

13 publications found

Variant links:

Genes affected

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CNOT1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
holoprosencephaly 12 with or without pancreatic agenesis
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
Vissers-Bodmer syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

CNOT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00601 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 16-58543411-GAA-G is Benign according to our data. Variant chr16-58543411-GAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2646576.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5 link	c.4434+194_4434+195delTT		intron_variant	Intron 31 of 48	ENST00000317147.10	NP_057368.3	A5YKK6-1
CNOT1	NM_206999.3 link	c.4628_4629delTT	p.Phe1543SerfsTer22	frameshift_variant	Exon 31 of 31		NP_996882.1	A5YKK6-4
CNOT1	NM_001265612.2 link	c.4419+194_4419+195delTT		intron_variant	Intron 31 of 48		NP_001252541.1	A5YKK6-2
CNOT1	NR_049763.2 link	n.4692+194_4692+195delTT		intron_variant	Intron 31 of 49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10 link	c.4434+194_4434+195delTT		intron_variant	Intron 31 of 48	1	NM_016284.5	ENSP00000320949.5		A5YKK6-1

Frequencies

GnomAD3 genomes

AF:

0.000462

AC:

AN:

129812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000859

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00136

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000533

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00345

AC:

235

AN:

68028

AF XY:

0.00386

show subpopulations

Gnomad AFR exome

AF:

0.000875

Gnomad AMR exome

AF:

0.00485

Gnomad ASJ exome

AF:

0.00426

Gnomad EAS exome

AF:

0.00208

Gnomad FIN exome

AF:

0.00241

Gnomad NFE exome

AF:

0.00378

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.000678

AC:

825

AN:

1216198

Hom.:

AF XY:

0.000713

AC XY:

423

AN XY:

593526

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000310

AC:

AN:

25808

American (AMR)

AF:

0.00229

AC:

AN:

19636

Ashkenazi Jewish (ASJ)

AF:

0.000621

AC:

AN:

19312

East Asian (EAS)

AF:

0.000848

AC:

AN:

33002

South Asian (SAS)

AF:

0.00159

AC:

AN:

59930

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

42342

Middle Eastern (MID)

AF:

0.000419

AC:

AN:

4772

European-Non Finnish (NFE)

AF:

0.000573

AC:

551

AN:

961084

Other (OTH)

AF:

0.000537

AC:

AN:

50312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000470

AC:

AN:

129878

Hom.:

Cov.:

AF XY:

0.000543

AC XY:

AN XY:

62592

show subpopulations

African (AFR)

AF:

0.000263

AC:

AN:

34244

American (AMR)

AF:

0.000446

AC:

AN:

13442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3182

East Asian (EAS)

AF:

0.000863

AC:

AN:

4634

South Asian (SAS)

AF:

0.00

AC:

AN:

4294

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

7354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000533

AC:

AN:

59986

Other (OTH)

AF:

0.00

AC:

AN:

1758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000361

Hom.:

176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Holoprosencephaly 12 with or without pancreatic agenesis

Uncertain:1

Apr 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CNOT1: BS1, BS2 -

CNOT1-related disorder

Benign:1

Jul 28, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=131/69

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over