16-84590253-C-A

Variant names:

• chr16-84590253-C-A
• rs747265049
• NM_021149.5:c.170G>T

Variant summary

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

The NM_021149.5(COTL1):​c.170G>T​(p.Arg57Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R57Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COTL1 NM_021149.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

Genes affected

COTL1 (HGNC:18304): (coactosin like F-actin binding protein 1) This gene encodes one of the numerous actin-binding proteins which regulate the actin cytoskeleton. This protein binds F-actin, and also interacts with 5-lipoxygenase, which is the first committed enzyme in leukotriene biosynthesis. Although this gene has been reported to map to chromosome 17 in the Smith-Magenis syndrome region, the best alignments for this gene are to chromosome 16. The Smith-Magenis syndrome region is the site of two related pseudogenes. [provided by RefSeq, Jul 2008]

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, 0.803

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021149.5. 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
	COTL1	NM_021149.5	MANE Select	c.170G>T	p.Arg57Leu	missense	Exon 3 of 4	NP_066972.1	A0A384MTY2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COTL1	ENST00000262428.5	TSL:1 MANE Select	c.170G>T	p.Arg57Leu	missense	Exon 3 of 4	ENSP00000262428.4	Q14019
	COTL1	ENST00000561707.1	TSL:1	n.227G>T		non_coding_transcript_exon	Exon 1 of 2
	COTL1	ENST00000564057.1	TSL:5	c.-38G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	ENSP00000457033.1	H3BT58

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.42
Sift	Benign	0.070	T
Sift4G	Uncertain	0.059	T
Polyphen		0.94	P
Vest4		0.88
MutPred		0.59		Loss of catalytic residue at R57 (P = 0.1371)
MVP		0.66
MPC		0.51
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.78

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: rs747265049; hg19: chr16-84623859;