Genetic Variant TNNI3K:c.2352-14274A>G (chr1-74525960-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_015978.3(TNNI3K):c.2352-14274A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 152,098 control chromosomes in the GnomAD database, including 18,225 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.48 ( 18225 hom., cov: 32)

Consequence

TNNI3K
NM_015978.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78

Publications

148 publications found

Variant links:

Genes affected

TNNI3K (HGNC:19661): (TNNI3 interacting kinase) This gene encodes a protein that belongs to the MAP kinase kinase kinase (MAPKKK) family of protein kinases. The protein contains ankyrin repeat, protein kinase and serine-rich domains and is thought to play a role in cardiac physiology. [provided by RefSeq, Sep 2012]

TNNI3K links:

FPGT-TNNI3K (HGNC:42952): (FPGT-TNNI3K readthrough) Enables protein C-terminus binding activity; protein kinase activity; and troponin I binding activity. Involved in protein phosphorylation and regulation of heart contraction. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FPGT-TNNI3K links:

LRRC53 (HGNC:25255): (leucine rich repeat containing 53) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC53 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3K	NM_015978.3	MANE Select	c.2352-14274A>G		intron	N/A	NP_057062.1
	FPGT-TNNI3K	NM_001112808.3		c.2655-14274A>G		intron	N/A	NP_001106279.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TNNI3K	ENST00000326637.8	TSL:1 MANE Select	c.2352-14274A>G	intron	N/A	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	TSL:2	c.2655-14274A>G	intron	N/A	ENSP00000450895.3
FPGT-TNNI3K	ENST00000648585.1		n.*2258-14274A>G	intron	N/A	ENSP00000497631.1

Frequencies

GnomAD3 genomes

AF:

0.477

AC:

72468

AN:

151980

Hom.:

18218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.453

Gnomad ASJ

AF:

0.617

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.517

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.572

Gnomad OTH

AF:

0.518

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.477

AC:

72491

AN:

152098

Hom.:

18225

Cov.:

AF XY:

0.471

AC XY:

34979

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.332

AC:

13756

AN:

41486

American (AMR)

AF:

0.452

AC:

6917

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

2141

AN:

3470

East Asian (EAS)

AF:

0.244

AC:

1260

AN:

5172

South Asian (SAS)

AF:

0.465

AC:

2242

AN:

4822

European-Finnish (FIN)

AF:

0.517

AC:

5453

AN:

10556

Middle Eastern (MID)

AF:

0.571

AC:

168

AN:

294

European-Non Finnish (NFE)

AF:

0.572

AC:

38891

AN:

67982

Other (OTH)

AF:

0.517

AC:

1089

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1907

3814

5720

7627

9534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.543

Hom.:

107514

Bravo

AF:

0.462

Asia WGS

AF:

0.397

AC:

1383

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over