NM_013354.7:c.378T>G

Variant names:

• chr8-17237307-A-C
• rs915272393
• NM_013354.7:c.378T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013354.7(CNOT7):​c.378T>G​(p.His126Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNOT7 NM_013354.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.631
• Publications: 0 publications found

Genes affected

CNOT7 (HGNC:14101): (CCR4-NOT transcription complex subunit 7) The protein encoded by this gene binds to an anti-proliferative protein, B-cell translocation protein 1, which negatively regulates cell proliferation. Binding of the two proteins, which is driven by phosphorylation of the anti-proliferative protein, causes signaling events in cell division that lead to changes in cell proliferation associated with cell-cell contact. The encoded protein downregulates the innate immune response and therefore provides a therapeutic target for enhancing its antimicrobial activity against foreign agents. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and X. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013354.7. 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
	CNOT7	NM_013354.7	MANE Select	c.378T>G	p.His126Gln	missense	Exon 4 of 7	NP_037486.2	Q9UIV1-1
	CNOT7	NM_001322093.2		c.444T>G	p.His148Gln	missense	Exon 5 of 8	NP_001309022.1
	CNOT7	NM_001322090.2		c.378T>G	p.His126Gln	missense	Exon 5 of 8	NP_001309019.1	Q9UIV1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT7	ENST00000361272.9	TSL:1 MANE Select	c.378T>G	p.His126Gln	missense	Exon 4 of 7	ENSP00000355279.4	Q9UIV1-1
	CNOT7	ENST00000851024.1		c.444T>G	p.His148Gln	missense	Exon 5 of 8	ENSP00000521093.1
	CNOT7	ENST00000851025.1		c.378T>G	p.His126Gln	missense	Exon 4 of 7	ENSP00000521094.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251444 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111918

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.63
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.35
Sift	Benign	0.032	D
Sift4G	Benign	0.069	T
Polyphen		0.97	D
Vest4		0.79
MutPred		0.63		Gain of ubiquitination at K124 (P = 0.1063)
MVP		0.71
MPC		1.4
ClinPred		0.95	D
GERP RS		1.2
Varity_R		0.79
gMVP		0.85
Mutation Taster		=37/63	disease causing

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: rs915272393; hg19: chr8-17094816;