chr3-32733520-A-G

Variant names:

• chr3-32733520-A-G
• NM_015442.3:c.1313A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015442.3(CNOT10):​c.1313A>G​(p.Gln438Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,160 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNOT10 NM_015442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.24
• 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]

CNOT10-AS1 (HGNC:41031): (CNOT10 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3965662).

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.1313A>G	p.Gln438Arg	missense	Exon 11 of 19	NP_056257.1	Q9H9A5-1
	CNOT10	NM_001256742.2		c.1493A>G	p.Gln498Arg	missense	Exon 11 of 19	NP_001243671.1	Q9H9A5-6
	CNOT10	NM_001393366.1		c.1313A>G	p.Gln438Arg	missense	Exon 11 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.1313A>G	p.Gln438Arg	missense	Exon 11 of 19	ENSP00000330060.5	Q9H9A5-1
	CNOT10	ENST00000331889.10	TSL:1	c.1313A>G	p.Gln438Arg	missense	Exon 11 of 18	ENSP00000329376.6	Q9H9A5-3
	CNOT10	ENST00000435630.5	TSL:1	n.1151A>G		non_coding_transcript_exon	Exon 10 of 17	ENSP00000402795.1	E9PCN5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441160 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 717890

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

African (AFR) AF: 0.00 AC: 0 AN: 33020

American (AMR) AF: 0.00 AC: 0 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 84916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5204

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095742

Other (OTH) AF: 0.00 AC: 0 AN: 59686

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	0.16
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.11	T
Sift4G	Benign	0.40	T
Polyphen		0.94	P
Vest4		0.58
MutPred		0.50		Gain of MoRF binding (P = 0.0116)
MVP		0.38
MPC		0.33
ClinPred		0.81	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.54
Mutation Taster		=34/66	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

hg19: chr3-32775012;