dbSNP rs2234933: CTF1:p.Ala92Thr (chr16-30902207-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A92E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CTF1
NM_001330.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.58

Publications

7 publications found

Variant links:

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]

CTF1 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CTF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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 VariationId is 44177.

BS2

High AC in GnomAd4 at 87 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CTF1	NM_001330.5	MANE Select	c.274G>A	p.Ala92Thr	missense	Exon 3 of 3	NP_001321.1
CTF1	NM_001142544.3		c.271G>A	p.Ala91Thr	missense	Exon 3 of 3	NP_001136016.1
CTF1	NR_165660.1		n.412G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTF1	ENST00000279804.3	TSL:1 MANE Select	c.274G>A	p.Ala92Thr	missense	Exon 3 of 3	ENSP00000279804.2
	CTF1	ENST00000395019.3	TSL:1	c.271G>A	p.Ala91Thr	missense	Exon 3 of 3	ENSP00000378465.3

Frequencies

GnomAD3 genomes

AF:

0.000583

AC:

AN:

149168

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

152

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ 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:

0.000220

AC:

225

AN:

1023520

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

117

AN XY:

484080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20610

American (AMR)

AF:

0.00

AC:

AN:

6380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11488

East Asian (EAS)

AF:

0.00

AC:

AN:

20644

South Asian (SAS)

AF:

0.00

AC:

AN:

19440

European-Finnish (FIN)

AF:

0.00373

AC:

AN:

18240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2588

European-Non Finnish (NFE)

AF:

0.000168

AC:

149

AN:

884994

Other (OTH)

AF:

0.000204

AC:

AN:

39136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000583

AC:

AN:

149280

Hom.:

Cov.:

AF XY:

0.000755

AC XY:

AN XY:

72858

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41212

American (AMR)

AF:

0.0000664

AC:

AN:

15050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00495

AC:

AN:

9496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000568

AC:

AN:

66892

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.000136

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Dilated Cardiomyopathy, Dominant (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.4

PhyloP100

1.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.70

REVEL

Uncertain

0.44

Sift

Benign

0.19

Sift4G

Benign

0.28

Polyphen

0.068

Vest4

0.11

MutPred

0.72

Loss of helix (P = 0.079)

MVP

0.81

MPC

0.45

ClinPred

0.12

GERP RS

2.8

Varity_R

0.051

gMVP

0.20

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over