rs753956418

Variant names:

• chr16-30899490-C-T
• rs753956418
• NM_001330.5:c.101C>T

Variant summary

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

The NM_001330.5(CTF1):​c.101C>T​(p.Ala34Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CTF1 NM_001330.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.89

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTF1	NM_001330.5	c.101C>T	p.Ala34Val	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.101C>T	p.Ala34Val	missense_variant	Exon 2 of 3	1	NM_001330.5	ENSP00000279804.2
CTF1	ENST00000395019.3	c.98C>T	p.Ala33Val	missense_variant	Exon 2 of 3	1		ENSP00000378465.3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250706 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135568

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461538 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151668 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74048

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101C>T (p.A34V) alteration is located in exon 2 (coding exon 2) of the CTF1 gene. This alteration results from a C to T substitution at nucleotide position 101, causing the alanine (A) at amino acid position 34 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated Cardiomyopathy, Dominant Uncertain:1

Sep 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the CTF1 protein (p.Ala34Val). This variant is present in population databases (rs753956418, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CTF1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.37		Gain of ubiquitination at K39 (P = 0.0931);.;
MVP		0.92
MPC		1.3
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.54
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753956418; hg19: chr16-30910811;