7-135438312-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001190850.2(CNOT4):​c.20C>A​(p.Ala7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054121822).

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>A	p.Ala7Glu	missense	Exon 2 of 12	NP_001177779.1
	CNOT4	NM_001393370.1		c.20C>A	p.Ala7Glu	missense	Exon 3 of 13	NP_001380299.1
	CNOT4	NM_001190849.2		c.20C>A	p.Ala7Glu	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>A	p.Ala7Glu	missense	Exon 2 of 12	ENSP00000445508.1
	CNOT4	ENST00000423368.6	TSL:1	c.20C>A	p.Ala7Glu	missense	Exon 2 of 11	ENSP00000406777.2
	CNOT4	ENST00000361528.8	TSL:1	c.20C>A	p.Ala7Glu	missense	Exon 2 of 11	ENSP00000354673.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244560 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456482 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 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: 9.01e-7 AC: 1 AN: 1109846

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.18
Sift	Benign	0.51	T
Sift4G	Benign	0.47	T
Polyphen		0.086	B
Vest4		0.25
MutPred		0.23		Gain of disorder (P = 0.0348)
MVP		0.68
MPC		1.8
ClinPred		0.056	T
GERP RS		1.6
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.60
Mutation Taster		=93/7	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;