16-58543411-GAAAAAA-GAAAAAAAAAA

Variant names:

• chr16-58543411-G-GAAAA
• rs5817153
• ENST00000441024.6:c.4626_4629dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_206999.3(CNOT1):​c.4626_4629dupTTTT​(p.Leu1544PhefsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,218,530 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: CNOT1 NM_206999.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Vissers-Bodmer syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0058 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206999.3. 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.4434+192_4434+195dupTTTT		intron	N/A	NP_057368.3
	CNOT1	NM_206999.3		c.4626_4629dupTTTT	p.Leu1544PhefsTer23	frameshift	Exon 31 of 31	NP_996882.1	A5YKK6-4
	CNOT1	NM_001265612.2		c.4419+192_4419+195dupTTTT		intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT1	ENST00000441024.6	TSL:1	c.4626_4629dupTTTT	p.Leu1544PhefsTer23	frameshift	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+192_4434+195dupTTTT		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.4419+192_4419+195dupTTTT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 8.21e-7 AC: 1 AN: 1218530 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 594662

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25830

American (AMR) AF: 0.00 AC: 0 AN: 19756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 33088

South Asian (SAS) AF: 0.00 AC: 0 AN: 60136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4784

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 962664

Other (OTH) AF: 0.00 AC: 0 AN: 50422

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.016

Splicing

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

Other links and lift over

dbSNP: rs5817153; hg19: chr16-58577315;