dbSNP rs1034195402: CTF1:p.Pro197Thr (chr16-30902522-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001330.5(CTF1):c.589C>A(p.Pro197Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CTF1
NM_001330.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.364

Publications

0 publications found

Variant links:

Genes affected

CTF1 (HGNC:2499): (cardiotrophin 1) The protein encoded by this gene is a secreted cytokine that induces cardiac myocyte hypertrophy in vitro. It has been shown to bind and activate the ILST/gp130 receoptor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

CTF1 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CTF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.21944892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTF1	NM_001330.5 link	c.589C>A	p.Pro197Thr	missense_variant	Exon 3 of 3	ENST00000279804.3	NP_001321.1	Q16619-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTF1	ENST00000279804.3 link	c.589C>A	p.Pro197Thr	missense_variant	Exon 3 of 3	1	NM_001330.5	ENSP00000279804.2		Q16619-1
CTF1	ENST00000395019.3 link	c.586C>A	p.Pro196Thr	missense_variant	Exon 3 of 3	1		ENSP00000378465.3		Q16619-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1344168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662466

African (AFR)

AF:

0.00

AC:

AN:

27794

American (AMR)

AF:

0.00

AC:

AN:

32792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23890

East Asian (EAS)

AF:

0.00

AC:

AN:

31216

South Asian (SAS)

AF:

0.00

AC:

AN:

76486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3946

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059320

Other (OTH)

AF:

0.00

AC:

AN:

55662

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 29, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with threonine at codon 197 of the CTF1 protein (p.Pro197Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CTF1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.52

T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.9

L;.

PhyloP100

-0.36

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.14

Sift

Benign

0.095

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.39

B;.

Vest4

0.18

MutPred

0.20

Gain of helix (P = 0.0425);.;

MVP

0.74

MPC

1.2

ClinPred

0.28

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.081

gMVP

0.11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over