7-135438312-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001190850.2(CNOT4):​c.20C>G​(p.Ala7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,608,360 control chromosomes in the GnomAD database, including 576 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.017 (30 hom., cov: 32)
  • Exomes 𝑓: 0.025 (546 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028414726).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0174 (2644/152218) while in subpopulation NFE AF = 0.0289 (1963/68016). AF 95% confidence interval is 0.0278. There are 30 homozygotes in GnomAd4. There are 1203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2644 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>G	p.Ala7Gly	missense	Exon 2 of 12	NP_001177779.1
	CNOT4	NM_001393370.1		c.20C>G	p.Ala7Gly	missense	Exon 3 of 13	NP_001380299.1
	CNOT4	NM_001190849.2		c.20C>G	p.Ala7Gly	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>G	p.Ala7Gly	missense	Exon 2 of 12	ENSP00000445508.1
	CNOT4	ENST00000423368.6	TSL:1	c.20C>G	p.Ala7Gly	missense	Exon 2 of 11	ENSP00000406777.2
	CNOT4	ENST00000361528.8	TSL:1	c.20C>G	p.Ala7Gly	missense	Exon 2 of 11	ENSP00000354673.4

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2644 AN: 152098 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00486

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0172 AC: 4211 AN: 244560 AF XY: 0.0172

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.00745

Gnomad ASJ exome AF: 0.00762

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0253 AC: 36808 AN: 1456142 Hom.: 546 Cov.: 30 AF XY: 0.0247 AC XY: 17879 AN XY: 724416

African (AFR) AF: 0.00389 AC: 129 AN: 33178

American (AMR) AF: 0.00871 AC: 379 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.00837 AC: 217 AN: 25920

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39594

South Asian (SAS) AF: 0.00203 AC: 173 AN: 85184

European-Finnish (FIN) AF: 0.0203 AC: 1083 AN: 53336

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5748

European-Non Finnish (NFE) AF: 0.0303 AC: 33566 AN: 1109522

Other (OTH) AF: 0.0205 AC: 1234 AN: 60166

GnomAD4 genome AF: 0.0174 AC: 2644 AN: 152218 Hom.: 30 Cov.: 32 AF XY: 0.0162 AC XY: 1203 AN XY: 74436

African (AFR) AF: 0.00484 AC: 201 AN: 41520

American (AMR) AF: 0.0124 AC: 190 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1963 AN: 68016

Other (OTH) AF: 0.0175 AC: 37 AN: 2110

Alfa AF: 0.0226 Hom.: 43

Bravo AF: 0.0168

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.00450 AC: 17

ESP6500EA AF: 0.0277 AC: 228

ExAC AF: 0.0167 AC: 2016

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.90	N
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		0.019	B
Vest4		0.083
MPC		1.6
ClinPred		0.011	T
GERP RS		1.6
PromoterAI		-0.021	Neutral
Varity_R		0.031
gMVP		0.40
Mutation Taster		=96/4	polymorphism (auto)

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: COSV59657290;