rs1043291296

Variant names:

• chr16-30899421-C-G
• rs1043291296
• NM_001330.5:c.32C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330.5(CTF1):​c.32C>G​(p.Pro11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CTF1 NM_001330.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.265

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 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=0.14634311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTF1	NM_001330.5	c.32C>G	p.Pro11Arg	missense_variant	Exon 2 of 3	ENST00000279804.3	NP_001321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTF1	ENST00000279804.3	c.32C>G	p.Pro11Arg	missense_variant	Exon 2 of 3	1	NM_001330.5	ENSP00000279804.2
CTF1	ENST00000395019.3	c.29C>G	p.Pro10Arg	missense_variant	Exon 2 of 3	1		ENSP00000378465.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250794 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135624

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456680 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the CTF1 protein (p.Pro11Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 567043). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; 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	0.092
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.29
Sift	Benign	0.15	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.70	P;.
Vest4		0.14
MutPred		0.093		Loss of loop (P = 0.0603);.;
MVP		0.86
MPC		1.1
ClinPred		0.51	D
GERP RS		2.8
Varity_R		0.094
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1043291296; hg19: chr16-30910742;