chr19-54155378-C-T

Variant names:

• chr19-54155378-C-T
• rs1451115570
• NM_014516.4:c.2233C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014516.4(CNOT3):​c.2233C>T​(p.Arg745Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• 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
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014516.4. 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
	CNOT3	NM_014516.4	MANE Select	c.2233C>T	p.Arg745Cys	missense	Exon 18 of 18	NP_055331.1	O75175
	LENG1	NM_024316.3	MANE Select	c.*343G>A		3_prime_UTR	Exon 4 of 4	NP_077292.2	Q96BZ8
	CNOT3	NM_001440653.1		c.2287C>T	p.Arg763Cys	missense	Exon 18 of 18	NP_001427582.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT3	ENST00000221232.11	TSL:1 MANE Select	c.2233C>T	p.Arg745Cys	missense	Exon 18 of 18	ENSP00000221232.5	O75175
	CNOT3	ENST00000358389.7	TSL:1	c.2233C>T	p.Arg745Cys	missense	Exon 17 of 17	ENSP00000351159.4	O75175
	LENG1	ENST00000222224.4	TSL:1 MANE Select	c.*343G>A		3_prime_UTR	Exon 4 of 4	ENSP00000222224.3	Q96BZ8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 245586 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.54		Loss of disorder (P = 0.0393)
MVP		0.38
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.69
gMVP		0.66
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1451115570; hg19: chr19-54659116;