chr16-58543411-G-GAAA

Variant names:

• chr16-58543411-G-GAAA
• rs5817153
• ENST00000441024.6:c.4627_4629dupTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_206999.3(CNOT1):​c.4627_4629dupTTT​(p.Phe1543dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,218,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CNOT1 NM_206999.3 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• Publications: 13 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_206999.3

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+193_4434+195dupTTT		intron	N/A	NP_057368.3
	CNOT1	NM_206999.3		c.4627_4629dupTTT	p.Phe1543dup	conservative_inframe_insertion	Exon 31 of 31	NP_996882.1	A5YKK6-4
	CNOT1	NM_001265612.2		c.4419+193_4419+195dupTTT		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.4627_4629dupTTT	p.Phe1543dup	conservative_inframe_insertion	Exon 31 of 31	ENSP00000413113.2	A5YKK6-4
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.4434+193_4434+195dupTTT		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.4419+193_4419+195dupTTT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000735 AC: 5 AN: 68028 AF XY: 0.0000284

Gnomad AFR exome AF: 0.000219

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000120

Gnomad NFE exome AF: 0.0000374

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.0000131 AC: 16 AN: 1218328 Hom.: 0 Cov.: 0 AF XY: 0.00000673 AC XY: 4 AN XY: 594568

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

African (AFR) AF: 0.0000387 AC: 1 AN: 25820

American (AMR) AF: 0.00 AC: 0 AN: 19748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 33086

South Asian (SAS) AF: 0.0000665 AC: 4 AN: 60120

European-Finnish (FIN) AF: 0.0000235 AC: 1 AN: 42482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4782

European-Non Finnish (NFE) AF: 0.0000104 AC: 10 AN: 962534

Other (OTH) AF: 0.00 AC: 0 AN: 50402

⚠️ 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;