4-77748336-C-A

Variant names:

• chr4-77748336-C-A
• rs199716504
• NM_144571.3:c.539G>T

Variant summary

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

The NM_144571.3(CNOT6L):​c.539G>T​(p.Arg180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R180Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNOT6L NM_144571.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• Publications: 0 publications found

Genes affected

CNOT6L (HGNC:18042): (CCR4-NOT transcription complex subunit 6 like) Predicted to enable poly(A)-specific ribonuclease activity. Involved in positive regulation of cell population proliferation and positive regulation of cytoplasmic mRNA processing body assembly. Located in cytosol and nucleus. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2786609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144571.3. 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
	CNOT6L	NM_144571.3	MANE Select	c.539G>T	p.Arg180Leu	missense	Exon 6 of 12	NP_653172.2	Q96LI5-1
	CNOT6L	NM_001387842.1		c.722G>T	p.Arg241Leu	missense	Exon 7 of 13	NP_001374771.1
	CNOT6L	NM_001387843.1		c.722G>T	p.Arg241Leu	missense	Exon 7 of 13	NP_001374772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNOT6L	ENST00000504123.7	TSL:2 MANE Select	c.539G>T	p.Arg180Leu	missense	Exon 6 of 12	ENSP00000424896.1	Q96LI5-1
	CNOT6L	ENST00000873612.1		c.539G>T	p.Arg180Leu	missense	Exon 6 of 12	ENSP00000543671.1
	CNOT6L	ENST00000512485.6	TSL:5	c.524G>T	p.Arg175Leu	missense	Exon 6 of 12	ENSP00000425571.2	H0Y9Z5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459880 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726326

⚠️ 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: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110704

Other (OTH) AF: 0.00 AC: 0 AN: 60292

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.095
Sift	Benign	0.15	T
Sift4G	Uncertain	0.037	D
Polyphen		0.19	B
Vest4		0.43
MutPred		0.48		Gain of catalytic residue at R180 (P = 0.0254)
MVP		0.15
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.81
Mutation Taster		=44/56	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: rs199716504; hg19: chr4-78669490;