Genetic Variant COTL1:p.Thr53Ala (chr16-84617504-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021149.5(COTL1):c.157A>G(p.Thr53Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,551,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COTL1
NM_021149.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Variant links:

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]

COTL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16135252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COTL1	NM_021149.5 link	c.157A>G	p.Thr53Ala	missense_variant	Exon 2 of 4	ENST00000262428.5	NP_066972.1	Q14019A0A384MTY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COTL1	ENST00000262428.5 link	c.157A>G	p.Thr53Ala	missense_variant	Exon 2 of 4	1	NM_021149.5	ENSP00000262428.4	Q14019
COTL1	ENST00000567786.2 link	c.55A>G	p.Thr19Ala	missense_variant	Exon 1 of 2	3		ENSP00000480117.1	A0A087WWC7
COTL1	ENST00000564057.1 link	c.-48+334A>G		intron_variant	Intron 1 of 2	5		ENSP00000457033.1	H3BT58
COTL1	ENST00000564662.1 link	n.572A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000101

AC:

AN:

158722

Hom.:

AF XY:

0.0000955

AC XY:

AN XY:

83738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000401

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000450

GnomAD4 exome

AF:

0.000114

AC:

159

AN:

1399958

Hom.:

Cov.:

AF XY:

0.0000956

AC XY:

AN XY:

690682

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.0000557

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000132

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000463

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157A>G (p.T53A) alteration is located in exon 2 (coding exon 2) of the COTL1 gene. This alteration results from a A to G substitution at nucleotide position 157, causing the threonine (T) at amino acid position 53 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.068

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

M_CAP

Benign

0.026

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

REVEL

Benign

0.10

Sift

Benign

0.82

Sift4G

Benign

0.76

Polyphen

0.0050

Vest4

0.51

MVP

0.55

MPC

0.31

ClinPred

0.074

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.52

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over