7-135364034-T-C

Position:

• chr7-135364034-T-C

Variant summary

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

The NM_001190850.2(CNOT4):​c.1660A>G​(p.Lys554Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,978 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

CNOT4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT4	NM_001190850.2	c.1660A>G	p.Lys554Glu	missense_variant	11/12	ENST00000541284.6	NP_001177779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT4	ENST00000541284.6	c.1660A>G	p.Lys554Glu	missense_variant	11/12	5	NM_001190850.2	ENSP00000445508.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445978 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719720

Gnomad4 AFR exome AF: 0.0000299

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.: 32

Bravo AF: 0.00000756

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

Oct 12, 2024

The c.1660A>G (p.K554E) alteration is located in exon 11 (coding exon 10) of the CNOT4 gene. This alteration results from a A to G substitution at nucleotide position 1660, causing the lysine (K) at amino acid position 554 to be replaced by a glutamic acid (E). 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
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.62	T;T
Vest4		0.72
MutPred		0.30		.;Loss of ubiquitination at K554 (P = 0.0134);
MVP		0.48
MPC		1.6
ClinPred		0.95	D
GERP RS		5.8
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

LitVar

Other links and lift over

dbSNP: rs919500954; hg19: chr7-135048786;