19-54154264-G-C

Variant names:

• chr19-54154264-G-C
• rs1055234
• NM_014516.4:c.2163+424G>C

Variant summary

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

The NM_014516.4(CNOT3):​c.2163+424G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 345,074 control chromosomes in the GnomAD database, including 56,313 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 0.59 (28317 hom., cov: 32)
  • Exomes 𝑓: 0.53 (27996 hom.)
• Consequence: CNOT3 NM_014516.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 9 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.2163+424G>C		intron_variant	Intron 17 of 17	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.2163+424G>C		intron_variant	Intron 17 of 17	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89971 AN: 151940 Hom.: 28280 Cov.: 32

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.581

GnomAD4 exome AF: 0.528 AC: 101866 AN: 193016 Hom.: 27996 Cov.: 0 AF XY: 0.539 AC XY: 56078 AN XY: 104024

African (AFR) AF: 0.802 AC: 4457 AN: 5554

American (AMR) AF: 0.635 AC: 6945 AN: 10940

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2830 AN: 4648

East Asian (EAS) AF: 0.642 AC: 5696 AN: 8874

South Asian (SAS) AF: 0.631 AC: 23592 AN: 37364

European-Finnish (FIN) AF: 0.475 AC: 4067 AN: 8564

Middle Eastern (MID) AF: 0.573 AC: 418 AN: 730

European-Non Finnish (NFE) AF: 0.458 AC: 48837 AN: 106718

Other (OTH) AF: 0.522 AC: 5024 AN: 9624

GnomAD4 genome AF: 0.592 AC: 90064 AN: 152058 Hom.: 28317 Cov.: 32 AF XY: 0.597 AC XY: 44342 AN XY: 74306

African (AFR) AF: 0.798 AC: 33106 AN: 41508

American (AMR) AF: 0.622 AC: 9500 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2107 AN: 3468

East Asian (EAS) AF: 0.650 AC: 3358 AN: 5164

South Asian (SAS) AF: 0.650 AC: 3132 AN: 4822

European-Finnish (FIN) AF: 0.502 AC: 5302 AN: 10554

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31775 AN: 67962

Other (OTH) AF: 0.578 AC: 1220 AN: 2110

Alfa AF: 0.353 Hom.: 789

Bravo AF: 0.610

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.6
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1055234; hg19: chr19-54658001;