7-135394131-A-T

Position:

• chr7-135394131-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001190850.2(CNOT4):​c.1414T>A​(p.Leu472Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

Genes affected

CNOT4 (HGNC:7880): (CCR4-NOT transcription complex subunit 4) The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1526798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT4	NM_001190850.2	c.1414T>A	p.Leu472Met	missense_variant	10/12	ENST00000541284.6	NP_001177779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT4	ENST00000541284.6	c.1414T>A	p.Leu472Met	missense_variant	10/12	5	NM_001190850.2	ENSP00000445508.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.1414T>A (p.L472M) alteration is located in exon 10 (coding exon 9) of the CNOT4 gene. This alteration results from a T to A substitution at nucleotide position 1414, causing the leucine (L) at amino acid position 472 to be replaced by a methionine (M). 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	Benign	0.082
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.027	.;.;.;.;.;T
Eigen	Benign	0.013
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;L;.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.23	N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.051	T;D;D;D;D;D
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.0050, 0.0030	.;.;B;B;B;B
Vest4		0.31
MutPred		0.23		.;Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);.;.;Gain of disorder (P = 0.0615);
MVP		0.59
MPC		0.58
ClinPred		0.31	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.31

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: chr7-135078883;