rs37060

Positions:

• chr16-58532400-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016284.5(CNOT1):​c.5896-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,610,182 control chromosomes in the GnomAD database, including 56,368 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4896 hom., cov: 33)
  • Exomes 𝑓: 0.26 (51472 hom.)
• Consequence: CNOT1 NM_016284.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000008593
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.590

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-58532400-G-A is Benign according to our data. Variant chr16-58532400-G-A is described in ClinVar as [Benign]. Clinvar id is 1217372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT1	NM_016284.5	c.5896-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.5881-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001252541.1
CNOT1	NR_049763.2	n.6154-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT1	ENST00000317147.10	c.5896-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016284.5	ENSP00000320949	P3

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36906 AN: 151982 Hom.: 4881 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.291 AC: 72945 AN: 250324 Hom.: 11647 AF XY: 0.286 AC XY: 38771 AN XY: 135336

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.452

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.384

Gnomad SAS exome AF: 0.319

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.260 AC: 379032 AN: 1458080 Hom.: 51472 Cov.: 33 AF XY: 0.261 AC XY: 189096 AN XY: 724590

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.243 AC: 36948 AN: 152102 Hom.: 4896 Cov.: 33 AF XY: 0.247 AC XY: 18368 AN XY: 74344

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.235

Alfa AF: 0.258 Hom.: 6211

Bravo AF: 0.245

Asia WGS AF: 0.353 AC: 1229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Vissers-Bodmer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Holoprosencephaly 12 with or without pancreatic agenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000086
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs37060; hg19: chr16-58566304; COSMIC: COSV55315818; COSMIC: COSV55315818;