chr7-135364052-C-T

Position:

• chr7-135364052-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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: 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT4	NM_001190850.2	c.1642G>A	p.Val548Ile	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.1642G>A	p.Val548Ile	missense_variant	11/12	5	NM_001190850.2	ENSP00000445508	A1

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

GnomAD3 exomes AF: 0.270 AC: 61690 AN: 228346 Hom.: 9389 AF XY: 0.261 AC XY: 32911 AN XY: 126250

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 SAS exome AF: 0.178

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

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.249

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

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.240

Alfa AF: 0.250 Hom.: 8440

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 v4.3

Name	Calibrated prediction	Score	Prediction
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;T
MetaRNN	Benign	0.00079	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.0045	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.14
Sift	Benign	0.78	T;T
Sift4G	Benign	0.64	T;T
Vest4		0.062
MPC		0.39
ClinPred		0.0078	T
GERP RS		5.0
gMVP		0.16

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

Publications

LitVar

Other links and lift over

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