chr16-30902280-C-T

Position:

• chr16-30902280-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330.5(CTF1):​c.347C>T​(p.Pro116Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,031,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CTF1 NM_001330.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039742887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTF1	NM_001330.5	c.347C>T	p.Pro116Leu	missense_variant	3/3	ENST00000279804.3	NP_001321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTF1	ENST00000279804.3	c.347C>T	p.Pro116Leu	missense_variant	3/3	1	NM_001330.5	ENSP00000279804	P3
CTF1	ENST00000395019.3	c.344C>T	p.Pro115Leu	missense_variant	3/3	1		ENSP00000378465	A1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146964 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 2 AN: 884346 Hom.: 0 Cov.: 30 AF XY: 0.00000483 AC XY: 2 AN XY: 414282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000345

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 146964 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71508

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.347C>T (p.P116L) alteration is located in exon 3 (coding exon 3) of the CTF1 gene. This alteration results from a C to T substitution at nucleotide position 347, causing the proline (P) at amino acid position 116 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CTF1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 116 of the CTF1 protein (p.Pro116Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.4
DANN	Benign	0.95
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.95	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.18
Sift	Benign	0.086	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0010	B;.
Vest4		0.052
MutPred		0.29		Loss of loop (P = 0.0128);.;
MVP		0.60
MPC		0.43
ClinPred		0.16	T
GERP RS		-6.5
Varity_R		0.052
gMVP		0.31

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

Other links and lift over

dbSNP: rs886051924; hg19: chr16-30913601;