16-58543411-GAAAAAA-GAAAAA

Variant names:

• chr16-58543411-GA-G
• rs5817153
• ENST00000441024.6:c.4629delT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_206999.3(CNOT1):​c.4629delT​(p.Leu1544CysfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,322,598 control chromosomes in the GnomAD database, including 8,091 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (4716 hom., cov: 21)
  • Exomes 𝑓: 0.25 (3375 hom.)
• Consequence: CNOT1 NM_206999.3 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0160
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 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-GA-G is Benign according to our data. Variant chr16-58543411-GA-G is described in ClinVar as Benign. ClinVar VariationId is 402549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	NM_016284.5	MANE Select	c.4434+195delT		intron	N/A	NP_057368.3
	CNOT1	NM_206999.3		c.4629delT	p.Leu1544CysfsTer11	frameshift	Exon 31 of 31	NP_996882.1	A5YKK6-4
	CNOT1	NM_001265612.2		c.4419+195delT		intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000441024.6	TSL:1	c.4629delT	p.Leu1544CysfsTer11	frameshift	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+195delT		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.4419+195delT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 36428 AN: 129714 Hom.: 4707 Cov.: 21

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.340 AC: 23153 AN: 68028 AF XY: 0.338

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.247 AC: 294644 AN: 1192822 Hom.: 3375 Cov.: 0 AF XY: 0.248 AC XY: 144263 AN XY: 582162

African (AFR) AF: 0.169 AC: 4234 AN: 25078

American (AMR) AF: 0.339 AC: 6597 AN: 19446

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 4548 AN: 18900

East Asian (EAS) AF: 0.308 AC: 9987 AN: 32424

South Asian (SAS) AF: 0.294 AC: 17341 AN: 59004

European-Finnish (FIN) AF: 0.279 AC: 11567 AN: 41392

Middle Eastern (MID) AF: 0.218 AC: 995 AN: 4560

European-Non Finnish (NFE) AF: 0.241 AC: 226952 AN: 942696

Other (OTH) AF: 0.252 AC: 12423 AN: 49322

GnomAD4 genome AF: 0.281 AC: 36455 AN: 129776 Hom.: 4716 Cov.: 21 AF XY: 0.289 AC XY: 18091 AN XY: 62542

African (AFR) AF: 0.200 AC: 6828 AN: 34220

American (AMR) AF: 0.381 AC: 5123 AN: 13430

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 860 AN: 3180

East Asian (EAS) AF: 0.410 AC: 1897 AN: 4626

South Asian (SAS) AF: 0.367 AC: 1576 AN: 4292

European-Finnish (FIN) AF: 0.342 AC: 2509 AN: 7344

Middle Eastern (MID) AF: 0.172 AC: 41 AN: 238

European-Non Finnish (NFE) AF: 0.282 AC: 16912 AN: 59944

Other (OTH) AF: 0.279 AC: 491 AN: 1758

Alfa AF: 0.105 Hom.: 176

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.016
Mutation Taster		=183/17	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5817153; hg19: chr16-58577315; COSMIC: COSV55312370; COSMIC: COSV55312370;