chr19-54155385-T-C

Variant names:

• chr19-54155385-T-C
• NM_014516.4:c.2240T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_014516.4(CNOT3):​c.2240T>C​(p.Leu747Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.40
• 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: Pathogenic. The variant received 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 19-54155385-T-C is Pathogenic according to our data. Variant chr19-54155385-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3387819.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2240T>C	p.Leu747Pro	missense	Exon 18 of 18	NP_055331.1	O75175
	LENG1	NM_024316.3	MANE Select	c.*336A>G		3_prime_UTR	Exon 4 of 4	NP_077292.2	Q96BZ8
	CNOT3	NM_001440653.1		c.2294T>C	p.Leu765Pro	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.2240T>C	p.Leu747Pro	missense	Exon 18 of 18	ENSP00000221232.5	O75175
	CNOT3	ENST00000358389.7	TSL:1	c.2240T>C	p.Leu747Pro	missense	Exon 17 of 17	ENSP00000351159.4	O75175
	LENG1	ENST00000222224.4	TSL:1 MANE Select	c.*336A>G		3_prime_UTR	Exon 4 of 4	ENSP00000222224.3	Q96BZ8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.90		Gain of disorder (P = 0.0151)
MVP		0.76
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=38/62	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

hg19: chr19-54659123;