dbSNP rs750523606: TNNI3K:p.Pro8Thr (chr1-74235473-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015978.3(TNNI3K):c.22C>A(p.Pro8Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000736 in 1,358,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TNNI3K
NM_015978.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.42

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3 link	c.22C>A	p.Pro8Thr	missense_variant	Exon 1 of 25	ENST00000326637.8	NP_057062.1	Q59H18-2
FPGT-TNNI3K	NM_001112808.3 link	c.344-629C>A		intron_variant	Intron 3 of 26		NP_001106279.3	V9GXZ4
FPGT-TNNI3K	NM_001199327.2 link	c.344-629C>A		intron_variant	Intron 3 of 23		NP_001186256.3	Q59H18-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3K	ENST00000326637.8 link	c.22C>A	p.Pro8Thr	missense_variant	Exon 1 of 25	1	NM_015978.3	ENSP00000322251.3		Q59H18-2
FPGT-TNNI3K	ENST00000557284.7 link	c.344-629C>A		intron_variant	Intron 3 of 26	2		ENSP00000450895.3		V9GXZ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1358714

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680414

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29778

American (AMR)

AF:

0.00

AC:

AN:

36874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24960

East Asian (EAS)

AF:

0.00

AC:

AN:

37814

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1034436

Other (OTH)

AF:

0.00

AC:

AN:

56608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.1

PhyloP100

4.4

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.41

Gain of MoRF binding (P = 0.035);

MVP

0.72

ClinPred

0.83

GERP RS

5.7

PromoterAI

0.0048

Neutral

(source)

Varity_R

0.23

gMVP

0.60

Mutation Taster

=27/73

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over