NM_016284.5:c.-174-4113G>C

Variant names:

• chr16-58603624-C-G
• rs4784051
• NM_016284.5:c.-174-4113G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016284.5(CNOT1):​c.-174-4113G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 151,922 control chromosomes in the GnomAD database, including 43,418 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43418 hom., cov: 30)
• Consequence: CNOT1 NM_016284.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Vissers-Bodmer syndrome

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016284.5. 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.-174-4113G>C		intron	N/A	NP_057368.3
	CNOT1	NM_001265612.2		c.-174-4113G>C		intron	N/A	NP_001252541.1	A5YKK6-2
	CNOT1	NM_206999.3		c.-174-4113G>C		intron	N/A	NP_996882.1	A5YKK6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.-174-4113G>C		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.-174-4113G>C		intron	N/A	ENSP00000455635.1	A5YKK6-2
	CNOT1	ENST00000441024.6	TSL:1	c.-174-4113G>C		intron	N/A	ENSP00000413113.2	A5YKK6-4

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114224 AN: 151800 Hom.: 43384 Cov.: 30

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.766

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.752 AC: 114304 AN: 151922 Hom.: 43418 Cov.: 30 AF XY: 0.747 AC XY: 55452 AN XY: 74218

African (AFR) AF: 0.841 AC: 34863 AN: 41444

American (AMR) AF: 0.650 AC: 9889 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2575 AN: 3468

East Asian (EAS) AF: 0.619 AC: 3198 AN: 5168

South Asian (SAS) AF: 0.664 AC: 3193 AN: 4806

European-Finnish (FIN) AF: 0.708 AC: 7456 AN: 10536

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50577 AN: 67968

Other (OTH) AF: 0.762 AC: 1609 AN: 2112

Alfa AF: 0.741 Hom.: 5225

Bravo AF: 0.753

Asia WGS AF: 0.648 AC: 2251 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.89
PhyloP100		0.11
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: rs4784051; hg19: chr16-58637528;