Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_015978.3(TNNI3K):c.1577G>A(p.Gly526Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TNNI3K
NM_015978.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.43

Publications

11 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:

ENSG00000237324 (HGNC:):

ENSG00000237324 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 1-74369495-G-A is Pathogenic according to our data. Variant chr1-74369495-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 161447.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNI3K	NM_015978.3	MANE Select	c.1577G>A	p.Gly526Asp	missense	Exon 16 of 25	NP_057062.1
FPGT-TNNI3K	NM_001112808.3		c.1880G>A	p.Gly627Asp	missense	Exon 18 of 27	NP_001106279.3
FPGT-TNNI3K	NM_001199327.2		c.1880G>A	p.Gly627Asp	missense	Exon 18 of 24	NP_001186256.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNI3K	ENST00000326637.8	TSL:1 MANE Select	c.1577G>A	p.Gly526Asp	missense	Exon 16 of 25	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	TSL:2	c.1880G>A	p.Gly627Asp	missense	Exon 18 of 27	ENSP00000450895.3
FPGT-TNNI3K	ENST00000370899.7	TSL:2	c.1880G>A	p.Gly627Asp	missense	Exon 18 of 24	ENSP00000359936.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atrial conduction disease (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.56

MutationAssessor

Benign

2.0

PhyloP100

9.4

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.97

MVP

0.92

MPC

0.21

ClinPred

1.0

GERP RS

5.3

PromoterAI

0.021

Neutral

(source)

Varity_R

0.97

gMVP

0.81

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs606231469

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over