rs2234933

Positions:

• chr16-30902207-G-A

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.274G>A​(p.Ala92Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,172,800 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: CTF1 NM_001330.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.58

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=0.060124815).
• BP6: Variant 16-30902207-G-A is Benign according to our data. Variant chr16-30902207-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44177.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTF1	NM_001330.5	c.274G>A	p.Ala92Thr	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.274G>A	p.Ala92Thr	missense_variant	3/3	1	NM_001330.5	ENSP00000279804	P3
CTF1	ENST00000395019.3	c.271G>A	p.Ala91Thr	missense_variant	3/3	1		ENSP00000378465	A1

Frequencies

GnomAD3 genomes AF: 0.000583 AC: 87 AN: 149168 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00495

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000568

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 225 AN: 1023520 Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 117 AN XY: 484080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00373

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000204

GnomAD4 genome AF: 0.000583 AC: 87 AN: 149280 Hom.: 1 Cov.: 31 AF XY: 0.000755 AC XY: 55 AN XY: 72858

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00495

Gnomad4 NFE AF: 0.000568

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2012	Variant classified as Uncertain Significance - Favor Benign. The Ala92Thr varian t in CTF1 has not been reported in the literature nor previously identified by o ur laboratory. This variant has been listed in dbSNP (rs2234933) without frequen cy information. Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. Additional information is needed to fully assess the clinical signifi cance of this variant. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2022	Variant summary: CTF1 c.274G>A (p.Ala92Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 147944 control chromosomes in the gnomAD v3.1.2 database, including 1 homozygote. The observed variant frequency is approximately 38-fold of the estimated maximal expected allele frequency for a pathogenic variant in CTF1 causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is benign. c.274G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Erdmann_2000, Akinrinade_2015). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance, while another ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as benign. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 16, 2015

- -

Dilated Cardiomyopathy, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.72	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.70	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.19	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.068	B;.
Vest4		0.11
MutPred		0.72		Loss of helix (P = 0.079);.;
MVP		0.81
MPC		0.45
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.051
gMVP		0.20

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: rs2234933; hg19: chr16-30913528;