rs397516648

Variant names:

• chr16-30902213-C-T
• rs397516648
• NM_001330.5:c.280C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001330.5(CTF1):​c.280C>T​(p.Leu94Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,160,236 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: CTF1 NM_001330.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.736

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-30902213-C-T is Benign according to our data. Variant chr16-30902213-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.736 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTF1	NM_001330.5	c.280C>T	p.Leu94Leu	synonymous_variant	Exon 3 of 3	ENST00000279804.3	NP_001321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTF1	ENST00000279804.3	c.280C>T	p.Leu94Leu	synonymous_variant	Exon 3 of 3	1	NM_001330.5	ENSP00000279804.2
CTF1	ENST00000395019.3	c.277C>T	p.Leu93Leu	synonymous_variant	Exon 3 of 3	1		ENSP00000378465.3

Frequencies

GnomAD3 genomes AF: 0.000504 AC: 75 AN: 148932 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000730

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000606 AC: 613 AN: 1011192 Hom.: 2 Cov.: 30 AF XY: 0.000603 AC XY: 288 AN XY: 477778

Gnomad4 AFR exome AF: 0.0000494

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.0000910

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.000660

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.000503 AC: 75 AN: 149044 Hom.: 1 Cov.: 31 AF XY: 0.000454 AC XY: 33 AN XY: 72716

Gnomad4 AFR AF: 0.0000728

Gnomad4 AMR AF: 0.000200

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000213

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000648 Hom.: 0

Bravo AF: 0.000468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 25, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu94Leu in exon 3 of CTF1: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. Leu94Leu in exon 3 of CTF1 (allele frequency = n/a) -

Mar 07, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CTF1 c.280C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00052 in 27054 control chromosomes. The observed variant frequency is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in CTF1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.280C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:1

Jun 01, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.92

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: rs397516648; hg19: chr16-30913534;