3-32716258-C-A

Variant names:

• chr3-32716258-C-A
• rs143945309
• NM_015442.3:c.607C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015442.3(CNOT10):​c.607C>A​(p.His203Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,603,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H203Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNOT10 NM_015442.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10529634).

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.607C>A	p.His203Asn	missense	Exon 6 of 19	NP_056257.1	Q9H9A5-1
	CNOT10	NM_001256742.2		c.787C>A	p.His263Asn	missense	Exon 6 of 19	NP_001243671.1	Q9H9A5-6
	CNOT10	NM_001393366.1		c.607C>A	p.His203Asn	missense	Exon 6 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.607C>A	p.His203Asn	missense	Exon 6 of 19	ENSP00000330060.5	Q9H9A5-1
	CNOT10	ENST00000331889.10	TSL:1	c.607C>A	p.His203Asn	missense	Exon 6 of 18	ENSP00000329376.6	Q9H9A5-3
	CNOT10	ENST00000435630.5	TSL:1	n.445C>A		non_coding_transcript_exon	Exon 5 of 17	ENSP00000402795.1	E9PCN5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000818 AC: 2 AN: 244512 AF XY: 0.00000756

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451252 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722094

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 43182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39202

South Asian (SAS) AF: 0.00 AC: 0 AN: 84496

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106380

Other (OTH) AF: 0.0000167 AC: 1 AN: 59988

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74254

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

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.056
Sift	Benign	0.15	T
Sift4G	Benign	0.48	T
Polyphen		0.0040	B
Vest4		0.26
MutPred		0.19		Gain of relative solvent accessibility (P = 0.1066)
MVP		0.24
MPC		0.30
ClinPred		0.29	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.33
Mutation Taster		=271/29	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: rs143945309; hg19: chr3-32757750;