chr3-32720121-C-T

Variant names:

• chr3-32720121-C-T
• rs755586827
• NM_015442.3:c.752C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015442.3(CNOT10):​c.752C>T​(p.Pro251Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000796 in 1,506,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CNOT10 NM_015442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

Genes affected

CNOT10 (HGNC:23817): (CCR4-NOT transcription complex subunit 10) Predicted to be involved in mRNA catabolic process and negative regulation of translation. Located in membrane. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41787907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015442.3. 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
	CNOT10	NM_015442.3	MANE Select	c.752C>T	p.Pro251Leu	missense	Exon 8 of 19	NP_056257.1	Q9H9A5-1
	CNOT10	NM_001256742.2		c.932C>T	p.Pro311Leu	missense	Exon 8 of 19	NP_001243671.1	Q9H9A5-6
	CNOT10	NM_001393366.1		c.752C>T	p.Pro251Leu	missense	Exon 8 of 19	NP_001380295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT10	ENST00000328834.10	TSL:1 MANE Select	c.752C>T	p.Pro251Leu	missense	Exon 8 of 19	ENSP00000330060.5	Q9H9A5-1
	CNOT10	ENST00000331889.10	TSL:1	c.752C>T	p.Pro251Leu	missense	Exon 8 of 18	ENSP00000329376.6	Q9H9A5-3
	CNOT10	ENST00000435630.5	TSL:1	n.590C>T		non_coding_transcript_exon	Exon 7 of 17	ENSP00000402795.1	E9PCN5

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249432 AF XY: 0.00000740

Gnomad AFR exome AF: 0.000127

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1354590 Hom.: 0 Cov.: 26 AF XY: 0.00000298 AC XY: 2 AN XY: 670146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000311 AC: 1 AN: 32164

American (AMR) AF: 0.00 AC: 0 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23824

East Asian (EAS) AF: 0.00 AC: 0 AN: 38878

South Asian (SAS) AF: 0.00 AC: 0 AN: 71934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5334

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1033946

Other (OTH) AF: 0.00 AC: 0 AN: 55116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.000242 AC: 10 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

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	Benign	0.23
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.20	T
Sift4G	Benign	0.39	T
Polyphen		0.015	B
Vest4		0.81
MutPred		0.34		Loss of loop (P = 0.0374)
MVP		0.36
MPC		0.38
ClinPred		0.35	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.77
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs755586827; hg19: chr3-32761613;