rs3812265

chr7-135364052-C-Gchr7-135364052-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001190850.2(CNOT4):c.1642G>C(p.Val548Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNOT4
• BP4: Computational evidence support a benign effect (MetaRNN=0.29927284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNOT4	NM_001190850.2	c.1642G>C	p.Val548Leu	missense_variant	11/12	ENST00000541284.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNOT4	ENST00000541284.6	c.1642G>C	p.Val548Leu	missense_variant	11/12	5	NM_001190850.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443466 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718458

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.89
Eigen	Benign	-0.21
Eigen_PC	Benign	0.0036
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.0013	P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.057
Sift	Benign	0.28	T;T
Sift4G	Benign	0.60	T;T
Vest4		0.30
MutPred		0.17		.;Gain of helix (P = 0.062);
MVP		0.42
MPC		0.48
ClinPred		0.90	D
GERP RS		5.0
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs3812265; hg19: chr7-135048804;