Genetic Variant COTL1:p.Thr28Ser (chr16-84617578-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021149.5(COTL1):c.83C>G(p.Thr28Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,402,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

COTL1
NM_021149.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.83C>G	p.Thr28Ser	missense	Exon 2 of 4	NP_066972.1	A0A384MTY2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COTL1	ENST00000262428.5	TSL:1 MANE Select	c.83C>G	p.Thr28Ser	missense	Exon 2 of 4	ENSP00000262428.4	Q14019
COTL1	ENST00000564057.1	TSL:5	c.-48+260C>G		intron	N/A	ENSP00000457033.1	H3BT58
COTL1	ENST00000564662.1	TSL:2	n.498C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000623

AC:

AN:

160414

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1402850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31882

American (AMR)

AF:

0.0000831

AC:

AN:

36086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36226

South Asian (SAS)

AF:

0.00

AC:

AN:

79492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080604

Other (OTH)

AF:

0.00

AC:

AN:

58140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

Eigen

Benign

0.059

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.67

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

PhyloP100

4.6

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Uncertain

0.015

Sift4G

Uncertain

0.029

Polyphen

0.059

Vest4

0.59

MutPred

0.55

Loss of ubiquitination at K30 (P = 0.1278)

MVP

0.53

MPC

0.39

ClinPred

0.46

GERP RS

4.7

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.62

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over