Genetic Variant CNOT1:p.Leu1544PhefsTer12 (chr16-58543411-G-GAA) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_ModerateBP6

The NM_206999.3(CNOT1):c.4628_4629dupTT(p.Leu1544PhefsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,342,700 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0000077 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

CNOT1
NM_206999.3 frameshift

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0160

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Vissers-Bodmer syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

CNOT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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 0.0058 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 16-58543411-G-GAA is Benign according to our data. Variant chr16-58543411-G-GAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3060733.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT1	NM_016284.5	MANE Select	c.4434+194_4434+195dupTT		intron	N/A	NP_057368.3
CNOT1	NM_206999.3		c.4628_4629dupTT	p.Leu1544PhefsTer12	frameshift	Exon 31 of 31	NP_996882.1	A5YKK6-4
CNOT1	NM_001265612.2		c.4419+194_4419+195dupTT		intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNOT1	ENST00000441024.6	TSL:1	c.4628_4629dupTT	p.Leu1544PhefsTer12	frameshift	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+194_4434+195dupTT		intron	N/A	ENSP00000320949.5	A5YKK6-1
CNOT1	ENST00000569240.5	TSL:1	c.4419+194_4419+195dupTT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes

AF:

0.00000770

AC:

AN:

129810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000136

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00215

AC:

146

AN:

68028

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.00306

Gnomad AMR exome

AF:

0.00190

Gnomad ASJ exome

AF:

0.00155

Gnomad EAS exome

AF:

0.00164

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00207

GnomAD4 exome

AF:

0.000423

AC:

513

AN:

1212824

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

282

AN XY:

591866

show subpopulations

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

African (AFR)

AF:

0.000663

AC:

AN:

25660

American (AMR)

AF:

0.00117

AC:

AN:

19632

Ashkenazi Jewish (ASJ)

AF:

0.000780

AC:

AN:

19238

East Asian (EAS)

AF:

0.000395

AC:

AN:

32920

South Asian (SAS)

AF:

0.00136

AC:

AN:

59652

European-Finnish (FIN)

AF:

0.000946

AC:

AN:

42304

Middle Eastern (MID)

AF:

0.000210

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.000308

AC:

295

AN:

958448

Other (OTH)

AF:

0.000558

AC:

AN:

50200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000770

AC:

AN:

129876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

62590

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

34242

American (AMR)

AF:

0.00

AC:

AN:

13442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3182

East Asian (EAS)

AF:

0.00

AC:

AN:

4636

South Asian (SAS)

AF:

0.00

AC:

AN:

4294

European-Finnish (FIN)

AF:

0.000136

AC:

AN:

7356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59982

Other (OTH)

AF:

0.00

AC:

AN:

1758

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CNOT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.016

Mutation Taster

=144/56

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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16-58543411-GAAAAAA-GAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over