rs154432

Variant names:

• chr16-58626589-G-A
• rs154432
• NM_016284.5:c.-175+3139C>T

Variant summary

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

The NM_016284.5(CNOT1):​c.-175+3139C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 151,330 control chromosomes in the GnomAD database, including 10,118 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 0.34 (10118 hom., cov: 29)
• Consequence: CNOT1 NM_016284.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.766
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.-175+3139C>T		intron_variant	Intron 1 of 48	ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.-175+3139C>T		intron_variant	Intron 1 of 48		NP_001252541.1
CNOT1	NM_206999.3	c.-175+3139C>T		intron_variant	Intron 1 of 30		NP_996882.1
CNOT1	NR_049763.2	n.99+3139C>T		intron_variant	Intron 1 of 49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.-175+3139C>T		intron_variant	Intron 1 of 48	1	NM_016284.5	ENSP00000320949.5

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51502 AN: 151212 Hom.: 10123 Cov.: 29

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.375

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

GnomAD4 genome AF: 0.340 AC: 51497 AN: 151330 Hom.: 10118 Cov.: 29 AF XY: 0.333 AC XY: 24594 AN XY: 73910

African (AFR) AF: 0.185 AC: 7649 AN: 41292

American (AMR) AF: 0.318 AC: 4828 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3464

East Asian (EAS) AF: 0.0323 AC: 166 AN: 5134

South Asian (SAS) AF: 0.235 AC: 1128 AN: 4800

European-Finnish (FIN) AF: 0.410 AC: 4257 AN: 10384

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30777 AN: 67784

Other (OTH) AF: 0.369 AC: 771 AN: 2088

Alfa AF: 0.384 Hom.: 1526

Bravo AF: 0.328

Asia WGS AF: 0.137 AC: 476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.5
DANN	Benign	0.80
PhyloP100		-0.77
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: rs154432; hg19: chr16-58660493;