16-30899472-G-A

Position:

chr16-30899472-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001330.5(CTF1):c.83G>A(p.Arg28His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,605,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

CTF1
NM_001330.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.189

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13170081).

BP6

Variant 16-30899472-G-A is Benign according to our data. Variant chr16-30899472-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 660206.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTF1	NM_001330.5 linkuse as main transcript	c.83G>A	p.Arg28His	missense_variant	2/3	ENST00000279804.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTF1	ENST00000279804.3 linkuse as main transcript	c.83G>A	p.Arg28His	missense_variant	2/3	1	NM_001330.5	P3	Q16619-1
CTF1	ENST00000395019.3 linkuse as main transcript	c.80G>A	p.Arg27His	missense_variant	2/3	1		A1	Q16619-2

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

151004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251206

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000770

AC:

112

AN:

1454446

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

723466

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000759

Gnomad4 NFE exome

AF:

0.0000894

Gnomad4 OTH exome

AF:

0.0000835

GnomAD4 genome

AF:

0.0000199

AC:

AN:

151004

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73664

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000965

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000721

Hom.:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 28 of the CTF1 protein (p.Arg28His). This variant is present in population databases (rs201703547, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CTF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 660206). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 24, 2020

Variant summary: CTF1 c.83G>A (p.Arg28His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251206 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.2-fold the estimated maximal expected allele frequency for a pathogenic variant in CTF1 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge,there are no reports of c.83G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function reported in the literature. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

0.57

D;D

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.18

Sift

Benign

0.26

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0070

B;.

Vest4

0.15

MutPred

0.27

Gain of ubiquitination at K26 (P = 0.0654);.;

MVP

0.76

MPC

0.53

ClinPred

0.092

GERP RS

1.0

Varity_R

0.036

gMVP

0.20

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