19-54155300-C-G

Variant names:

• chr19-54155300-C-G
• NM_024316.3:c.*421G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024316.3(LENG1):​c.*421G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LENG1 NM_024316.3 3_prime_UTR
• Scores: Splicing: ADA: 0.4665
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

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

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1266467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3	c.*421G>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2
CNOT3	NM_014516.4	c.2164-9C>G		intron_variant	Intron 17 of 17	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LENG1	ENST00000222224.4	c.*421G>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3
CNOT3	ENST00000221232.11	c.2164-9C>G		intron_variant	Intron 17 of 17	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CNOT3-related disorder Uncertain:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CNOT3 c.2164-9C>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.50	N
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.065
Sift	Benign	0.045	D
Sift4G	Benign	0.063	T
MutPred		0.29		Gain of catalytic residue at P54 (P = 0.0045);
MVP		0.15
ClinPred		0.23	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -42

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

Other links and lift over

hg19: chr19-54659038;