NM_016284.5:c.3201+124G>T

Variant names:

• chr16-58551465-C-A
• rs7184114
• NM_016284.5:c.3201+124G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016284.5(CNOT1):​c.3201+124G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,247,326 control chromosomes in the GnomAD database, including 287,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (38211 hom., cov: 32)
  • Exomes 𝑓: 0.67 (249497 hom.)
• Consequence: CNOT1 NM_016284.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.287
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-58551465-C-A is Benign according to our data. Variant chr16-58551465-C-A is described in ClinVar as Benign. ClinVar VariationId is 1250890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.3201+124G>T		intron_variant	Intron 23 of 48	ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.3186+124G>T		intron_variant	Intron 23 of 48		NP_001252541.1
CNOT1	NM_206999.3	c.3201+124G>T		intron_variant	Intron 23 of 30		NP_996882.1
CNOT1	NR_049763.2	n.3459+124G>T		intron_variant	Intron 23 of 49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.3201+124G>T		intron_variant	Intron 23 of 48	1	NM_016284.5	ENSP00000320949.5

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106855 AN: 151962 Hom.: 38176 Cov.: 32

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.703

GnomAD4 exome AF: 0.672 AC: 735603 AN: 1095246 Hom.: 249497 AF XY: 0.670 AC XY: 367056 AN XY: 548158

African (AFR) AF: 0.840 AC: 20757 AN: 24708

American (AMR) AF: 0.527 AC: 15859 AN: 30106

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 12393 AN: 19238

East Asian (EAS) AF: 0.645 AC: 23634 AN: 36622

South Asian (SAS) AF: 0.591 AC: 37914 AN: 64138

European-Finnish (FIN) AF: 0.645 AC: 28108 AN: 43610

Middle Eastern (MID) AF: 0.672 AC: 2166 AN: 3222

European-Non Finnish (NFE) AF: 0.682 AC: 563214 AN: 826272

Other (OTH) AF: 0.667 AC: 31558 AN: 47330

GnomAD4 genome AF: 0.703 AC: 106935 AN: 152080 Hom.: 38211 Cov.: 32 AF XY: 0.697 AC XY: 51845 AN XY: 74342

African (AFR) AF: 0.829 AC: 34412 AN: 41510

American (AMR) AF: 0.602 AC: 9196 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2257 AN: 3466

East Asian (EAS) AF: 0.618 AC: 3197 AN: 5174

South Asian (SAS) AF: 0.586 AC: 2827 AN: 4824

European-Finnish (FIN) AF: 0.642 AC: 6781 AN: 10560

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.676 AC: 45927 AN: 67952

Other (OTH) AF: 0.700 AC: 1476 AN: 2110

Alfa AF: 0.686 Hom.: 52128

Bravo AF: 0.708

Asia WGS AF: 0.621 AC: 2157 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.2
DANN	Benign	0.25
PhyloP100		0.29
PromoterAI		0.0014	Neutral
Mutation Taster		=100/0	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: rs7184114; hg19: chr16-58585369; COSMIC: COSV55323759; COSMIC: COSV55323759;