19-54155397-ACCTCCAGTGACACCGGCC-A

Variant names:

• chr19-54155397-ACCTCCAGTGACACCGGCC-A
• NM_014516.4:c.2258_*13delAGTGACACCGGCCCCTCC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM4

The NM_014516.4(CNOT3):​c.2258_*13delAGTGACACCGGCCCCTCC​(p.Gln753_Ter754delins???) variant causes a stop lost, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT3 NM_014516.4 stop_lost, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20
• Publications: 0 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]

LENG1 (HGNC:15502): (leukocyte receptor cluster member 1)

ACMG classification

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

• PM1: In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_014516.4
• PM4: Stoplost variant in NM_014516.4 Downstream stopcodon found after 847 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.2258_*13delAGTGACACCGGCCCCTCC	p.Gln753_Ter754delins???	stop_lost, conservative_inframe_deletion	Exon 18 of 18	ENST00000221232.11	NP_055331.1
CNOT3	NM_014516.4	c.2258_*13delAGTGACACCGGCCCCTCC		3_prime_UTR_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1
LENG1	NM_024316.3	c.*306_*323delGGCCGGTGTCACTGGAGG		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.2258_*13delAGTGACACCGGCCCCTCC	p.Gln753_Ter754delins???	stop_lost, conservative_inframe_deletion	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
CNOT3	ENST00000221232.11	c.2258_*13delAGTGACACCGGCCCCTCC		3_prime_UTR_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
LENG1	ENST00000222224.4	c.*306_*323delGGCCGGTGTCACTGGAGG		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNOT3 c.2258_*13del18 (p.Gln753_X754delext4) results in an in-frame deletion of 18 nucleotides within the last exon (exon 18) in the region encompassing the stop codon, resulting in a protein extension. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.2258_*13del18 in individuals affected with Intellectual Developmental Disorder With Speech Delay, Autism, And Dysmorphic Facies and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

Other links and lift over

hg19: chr19-54659135;