rs37060

Variant names:

• chr16-58532400-G-A
• rs37060
• NM_016284.5:c.5896-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-58532400-G-A
• chr16-58532400-G-C
• chr16-58532400-G-T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.000008593
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.590
• Publications: 40 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 -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 VariationId 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.

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.5896-5C>T		splice_region intron	N/A	NP_057368.3
	CNOT1	NM_001265612.2		c.5881-5C>T		splice_region intron	N/A	NP_001252541.1	A5YKK6-2
	CNOT1	NR_049763.2		n.6154-5C>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.5896-5C>T		splice_region intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.5881-5C>T		splice_region intron	N/A	ENSP00000455635.1	A5YKK6-2
	CNOT1	ENST00000567188.5	TSL:1	n.5881-5C>T		splice_region intron	N/A	ENSP00000456649.1	A5YKK6-3

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

GnomAD2 exomes AF: 0.291 AC: 72945 AN: 250324 AF XY: 0.286

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 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

African (AFR) AF: 0.148 AC: 4934 AN: 33396

American (AMR) AF: 0.438 AC: 19531 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6717 AN: 26086

East Asian (EAS) AF: 0.354 AC: 13993 AN: 39544

South Asian (SAS) AF: 0.319 AC: 27476 AN: 86142

European-Finnish (FIN) AF: 0.266 AC: 14153 AN: 53288

Middle Eastern (MID) AF: 0.207 AC: 1189 AN: 5742

European-Non Finnish (NFE) AF: 0.248 AC: 275166 AN: 1109036

Other (OTH) AF: 0.263 AC: 15873 AN: 60254

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

African (AFR) AF: 0.158 AC: 6565 AN: 41486

American (AMR) AF: 0.349 AC: 5336 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3468

East Asian (EAS) AF: 0.381 AC: 1968 AN: 5162

South Asian (SAS) AF: 0.336 AC: 1619 AN: 4822

European-Finnish (FIN) AF: 0.257 AC: 2711 AN: 10564

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17098 AN: 68004

Other (OTH) AF: 0.235 AC: 496 AN: 2110

Alfa AF: 0.253 Hom.: 11466

Bravo AF: 0.245

Asia WGS AF: 0.353 AC: 1229 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Holoprosencephaly 12 with or without pancreatic agenesis (1)
-	-	1	Vissers-Bodmer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.43
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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