16-58543411-GAAAAAA-GAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The ENST00000441024.6(CNOT1):​c.4629dupT​(p.Leu1544SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,089,636 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 21)
  • Exomes 𝑓: 0.16 (0 hom.)
• Consequence: CNOT1 ENST00000441024.6 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• Vissers-Bodmer syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 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-GA is Benign according to our data. Variant chr16-58543411-G-GA is described in ClinVar as [Benign]. Clinvar id is 587551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.4434+195dupT		intron_variant	Intron 31 of 48	ENST00000317147.10	NP_057368.3
CNOT1	NM_206999.3	c.4629dupT	p.Leu1544SerfsTer22	frameshift_variant	Exon 31 of 31		NP_996882.1
CNOT1	NM_001265612.2	c.4419+195dupT		intron_variant	Intron 31 of 48		NP_001252541.1
CNOT1	NR_049763.2	n.4692+195dupT		intron_variant	Intron 31 of 49

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 405 AN: 129714 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00358

Gnomad ASJ AF: 0.00126

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00139

Gnomad FIN AF: 0.00177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00214

Gnomad OTH AF: 0.00691

GnomAD2 exomes AF: 0.148 AC: 10061 AN: 68028 AF XY: 0.150

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.159 AC: 152156 AN: 959856 Hom.: 0 Cov.: 0 AF XY: 0.159 AC XY: 74431 AN XY: 469534

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

African (AFR) AF: 0.228 AC: 4350 AN: 19094

American (AMR) AF: 0.112 AC: 1977 AN: 17702

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 2541 AN: 15478

East Asian (EAS) AF: 0.119 AC: 3294 AN: 27598

South Asian (SAS) AF: 0.142 AC: 7521 AN: 53026

European-Finnish (FIN) AF: 0.128 AC: 4599 AN: 35874

Middle Eastern (MID) AF: 0.129 AC: 514 AN: 3980

European-Non Finnish (NFE) AF: 0.162 AC: 121064 AN: 747128

Other (OTH) AF: 0.157 AC: 6296 AN: 39976

⚠️ 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.

GnomAD4 genome AF: 0.00316 AC: 410 AN: 129780 Hom.: 1 Cov.: 21 AF XY: 0.00350 AC XY: 219 AN XY: 62528

African (AFR) AF: 0.00552 AC: 189 AN: 34242

American (AMR) AF: 0.00357 AC: 48 AN: 13432

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 4 AN: 3182

East Asian (EAS) AF: 0.00194 AC: 9 AN: 4632

South Asian (SAS) AF: 0.00116 AC: 5 AN: 4294

European-Finnish (FIN) AF: 0.00177 AC: 13 AN: 7350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00214 AC: 128 AN: 59908

Other (OTH) AF: 0.00797 AC: 14 AN: 1756

Alfa AF: 0.00 Hom.: 176

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.016
Mutation Taster		=123/77	polymorphism

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: COSV55313050; COSMIC: COSV55313050;