Genetic Variant CNOT1:p.Phe1543del (chr16-58543411-GAAA-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_206999.3(CNOT1):c.4627_4629delTTT(p.Phe1543del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000492 in 1,218,522 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CNOT1
NM_206999.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_206999.3

BS2

High AC in GnomAdExome4 at 6 AD gene.

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+193_4434+195delTTT		intron	N/A	NP_057368.3
CNOT1	NM_206999.3		c.4627_4629delTTT	p.Phe1543del	conservative_inframe_deletion	Exon 31 of 31	NP_996882.1	A5YKK6-4
CNOT1	NM_001265612.2		c.4419+193_4419+195delTTT		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.4627_4629delTTT	p.Phe1543del	conservative_inframe_deletion	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+193_4434+195delTTT		intron	N/A	ENSP00000320949.5	A5YKK6-1
CNOT1	ENST00000569240.5	TSL:1	c.4419+193_4419+195delTTT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1218522

Hom.:

AF XY:

0.00000841

AC XY:

AN XY:

594662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25830

American (AMR)

AF:

0.0000506

AC:

AN:

19756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19356

East Asian (EAS)

AF:

0.0000302

AC:

AN:

33088

South Asian (SAS)

AF:

0.00

AC:

AN:

60142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4784

European-Non Finnish (NFE)

AF:

0.00000416

AC:

AN:

962650

Other (OTH)

AF:

0.00

AC:

AN:

50420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

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

Cov.:

Alfa

AF:

0.00

Hom.:

176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=85/15

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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16-58543411-GAAAAAA-GAAA

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