19-54142930-G-A

Variant names:

• chr19-54142930-G-A
• rs150786079
• NM_014516.4:c.-49G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_014516.4(CNOT3):​c.-49G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,597,910 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (35 hom.)
• Consequence: CNOT3 NM_014516.4 splice_region
• Scores: Splicing: ADA: 0.002778
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.258
• Publications: 3 publications found

Genes affected

CNOT3 (HGNC:7879): (CCR4-NOT transcription complex subunit 3) Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with speech delay, autism, and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE 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=-0.32).
• BP6: Variant 19-54142930-G-A is Benign according to our data. Variant chr19-54142930-G-A is described in ClinVar as [Benign]. Clinvar id is 1879454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00412 (628/152264) while in subpopulation AMR AF = 0.0068 (104/15300). AF 95% confidence interval is 0.00574. There are 2 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 628 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.-49G>A		splice_region_variant	Exon 2 of 18	ENST00000221232.11	NP_055331.1
CNOT3	NM_014516.4	c.-49G>A		5_prime_UTR_variant	Exon 2 of 18	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.-49G>A		splice_region_variant	Exon 2 of 18	1	NM_014516.4	ENSP00000221232.5
CNOT3	ENST00000221232.11	c.-49G>A		5_prime_UTR_variant	Exon 2 of 18	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00460

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00489 AC: 1224 AN: 250424 AF XY: 0.00524

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000909

Gnomad NFE exome AF: 0.00500

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00449 AC: 6492 AN: 1445646 Hom.: 35 Cov.: 29 AF XY: 0.00475 AC XY: 3423 AN XY: 720282

African (AFR) AF: 0.00205 AC: 68 AN: 33154

American (AMR) AF: 0.00680 AC: 304 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 446 AN: 26052

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.00509 AC: 438 AN: 85978

European-Finnish (FIN) AF: 0.000571 AC: 30 AN: 52528

Middle Eastern (MID) AF: 0.0158 AC: 90 AN: 5696

European-Non Finnish (NFE) AF: 0.00433 AC: 4755 AN: 1098068

Other (OTH) AF: 0.00601 AC: 360 AN: 59854

GnomAD4 genome AF: 0.00412 AC: 628 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74452

African (AFR) AF: 0.00176 AC: 73 AN: 41540

American (AMR) AF: 0.00680 AC: 104 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00460 AC: 313 AN: 68020

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00534 Hom.: 14

Bravo AF: 0.00458

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CNOT3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		0.26
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
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: rs150786079; hg19: chr19-54646666;