chr7-135438312-G-A

Variant names:

• chr7-135438312-G-A
• rs17480616
• NM_001190850.2:c.20C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001190850.2(CNOT4):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,608,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CNOT4 NM_001190850.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 20 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052098006).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT4	NM_001190850.2	MANE Select	c.20C>T	p.Ala7Val	missense	Exon 2 of 12	NP_001177779.1
	CNOT4	NM_001393370.1		c.20C>T	p.Ala7Val	missense	Exon 3 of 13	NP_001380299.1
	CNOT4	NM_001190849.2		c.20C>T	p.Ala7Val	missense	Exon 2 of 12	NP_001177778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT4	ENST00000541284.6	TSL:5 MANE Select	c.20C>T	p.Ala7Val	missense	Exon 2 of 12	ENSP00000445508.1
	CNOT4	ENST00000423368.6	TSL:1	c.20C>T	p.Ala7Val	missense	Exon 2 of 11	ENSP00000406777.2
	CNOT4	ENST00000361528.8	TSL:1	c.20C>T	p.Ala7Val	missense	Exon 2 of 11	ENSP00000354673.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 244560 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456482 Hom.: 0 Cov.: 30 AF XY: 0.00000690 AC XY: 5 AN XY: 724550

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109846

Other (OTH) AF: 0.0000332 AC: 2 AN: 60174

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 43

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.35	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.023
MutPred		0.16		Loss of glycosylation at P5 (P = 0.106)
MVP		0.52
MPC		1.4
ClinPred		0.056	T
GERP RS		1.6
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.40
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs17480616; hg19: chr7-135123060; COSMIC: COSV104409525;