rs1467275471

chr16-30902387-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001330.5(CTF1):c.454G>C(p.Ala152Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,239,092 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A152A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CTF1 NM_001330.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0780

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026454061).
• BP6: Variant 16-30902387-G-C is Benign according to our data. Variant chr16-30902387-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478119.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTF1	NM_001330.5	c.454G>C	p.Ala152Pro	missense_variant	3/3	ENST00000279804.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTF1	ENST00000279804.3	c.454G>C	p.Ala152Pro	missense_variant	3/3	1	NM_001330.5	P3
CTF1	ENST00000395019.3	c.451G>C	p.Ala151Pro	missense_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 6 AN: 149850 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000743

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 7 AN: 1089242 Hom.: 0 Cov.: 30 AF XY: 0.00000765 AC XY: 4 AN XY: 522798

Gnomad4 AFR exome AF: 0.0000454

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000339

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000433

Gnomad4 OTH exome AF: 0.0000235

GnomAD4 genome AF: 0.0000400 AC: 6 AN: 149850 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73086

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000743

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

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. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 152 of the CTF1 protein (p.Ala152Pro). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 478119). 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 proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.73
Dann	Benign	0.72
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	2.9	N;N
REVEL	Benign	0.086
Sift	Benign	0.91	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;.
Vest4		0.048
MutPred		0.32		Gain of glycosylation at A152 (P = 0.0174);.;
MVP		0.34
MPC		0.55
ClinPred		0.070	T
GERP RS		-0.072
Varity_R		0.062
gMVP		0.19

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: rs1467275471; hg19: chr16-30913708;