7-135364052-C-T

Variant names:

• chr7-135364052-C-T
• rs3812265
• NM_001190850.2:c.1642G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001190850.2(CNOT4):​c.1642G>A​(p.Val548Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,593,110 control chromosomes in the GnomAD database, including 51,994 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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: 𝑓 0.24 (4652 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47342 hom.)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.902384E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190850.2. 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
	CNOT4	NM_001190850.2	MANE Select	c.1642G>A	p.Val548Ile	missense	Exon 11 of 12	NP_001177779.1	O95628-10
	CNOT4	NM_001393370.1		c.1642G>A	p.Val548Ile	missense	Exon 12 of 13	NP_001380299.1	O95628-10
	CNOT4	NM_001190849.2		c.1633G>A	p.Val545Ile	missense	Exon 11 of 12	NP_001177778.1	O95628-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT4	ENST00000541284.6	TSL:5 MANE Select	c.1642G>A	p.Val548Ile	missense	Exon 11 of 12	ENSP00000445508.1	O95628-10
	CNOT4	ENST00000423368.6	TSL:1	c.1628-866G>A		intron	N/A	ENSP00000406777.2	O95628-4
	CNOT4	ENST00000361528.8	TSL:1	c.1619-866G>A		intron	N/A	ENSP00000354673.4	O95628-8

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36166 AN: 151602 Hom.: 4650 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.270 AC: 61690 AN: 228346 AF XY: 0.261

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.524

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.249 AC: 358926 AN: 1441390 Hom.: 47342 Cov.: 31 AF XY: 0.246 AC XY: 176320 AN XY: 717494

African (AFR) AF: 0.184 AC: 6144 AN: 33376

American (AMR) AF: 0.350 AC: 15592 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6035 AN: 26068

East Asian (EAS) AF: 0.500 AC: 19823 AN: 39650

South Asian (SAS) AF: 0.181 AC: 15552 AN: 85930

European-Finnish (FIN) AF: 0.248 AC: 9427 AN: 38008

Middle Eastern (MID) AF: 0.155 AC: 889 AN: 5752

European-Non Finnish (NFE) AF: 0.244 AC: 270505 AN: 1107928

Other (OTH) AF: 0.249 AC: 14959 AN: 60106

GnomAD4 genome AF: 0.239 AC: 36201 AN: 151720 Hom.: 4652 Cov.: 31 AF XY: 0.239 AC XY: 17739 AN XY: 74132

African (AFR) AF: 0.184 AC: 7604 AN: 41350

American (AMR) AF: 0.287 AC: 4372 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 814 AN: 3468

East Asian (EAS) AF: 0.519 AC: 2674 AN: 5152

South Asian (SAS) AF: 0.176 AC: 839 AN: 4778

European-Finnish (FIN) AF: 0.238 AC: 2493 AN: 10488

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.245 AC: 16648 AN: 67918

Other (OTH) AF: 0.240 AC: 506 AN: 2112

Alfa AF: 0.250 Hom.: 17229

Bravo AF: 0.243

TwinsUK AF: 0.239 AC: 888

ALSPAC AF: 0.248 AC: 955

ESP6500AA AF: 0.201 AC: 352

ESP6500EA AF: 0.250 AC: 996

ExAC AF: 0.263 AC: 30036

Asia WGS AF: 0.343 AC: 1190 AN: 3478

EpiCase AF: 0.231

EpiControl AF: 0.225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.76
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.00079	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.14
Sift	Benign	0.78	T
Sift4G	Benign	0.64	T
Vest4		0.062
MPC		0.39
ClinPred		0.0078	T
GERP RS		5.0
gMVP		0.16
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs3812265; hg19: chr7-135048804; COSMIC: COSV64158393;