19-54155394-G-C

Variant names:

• chr19-54155394-G-C
• NM_014516.4:c.2249G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014516.4(CNOT3):​c.2249G>C​(p.Arg750Pro) variant causes a missense change involving the alteration of a 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_014516.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.2249G>C	p.Arg750Pro	missense_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1
LENG1	NM_024316.3	c.*327C>G		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.2249G>C	p.Arg750Pro	missense_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
LENG1	ENST00000222224	c.*327C>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449110 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2249G>C (p.R750P) alteration is located in exon 18 (coding exon 17) of the CNOT3 gene. This alteration results from a G to C substitution at nucleotide position 2249, causing the arginine (R) at amino acid position 750 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.33		Gain of loop (P = 0.024);Gain of loop (P = 0.024);.;
MVP		0.51
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54659132;