dbSNP rs1211423908: TNNI3K:p.Ser6_Arg7del (chr1-74235485-TGTACTG-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The ENST00000326637.8(TNNI3K):c.16_21delGTACTG(p.Ser6_Arg7del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000152 in 1,312,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TNNI3K
ENST00000326637.8 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000326637.8.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3 link	c.38_40+3delCTGGTA	p.Thr13_Asp14delinsAsn	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 1 of 25	ENST00000326637.8	NP_057062.1	Q59H18-2
FPGT-TNNI3K	NM_001112808.3 link	c.344-613_344-608delCTGGTA		intron_variant	Intron 3 of 26		NP_001106279.3	V9GXZ4
FPGT-TNNI3K	NM_001199327.2 link	c.344-613_344-608delCTGGTA		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.16_21delGTACTG	p.Ser6_Arg7del	conservative_inframe_deletion	Exon 1 of 25	1	NM_015978.3	ENSP00000322251.3		Q59H18-2
FPGT-TNNI3K	ENST00000557284.7 link	c.344-635_344-630delGTACTG		intron_variant	Intron 3 of 26	2		ENSP00000450895.3		V9GXZ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000451

AC:

AN:

221658

AF XY:

0.00000826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000944

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1312220

Hom.:

AF XY:

0.00000303

AC XY:

AN XY:

659570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28684

American (AMR)

AF:

0.00

AC:

AN:

35572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24560

East Asian (EAS)

AF:

0.00

AC:

AN:

37502

South Asian (SAS)

AF:

0.00

AC:

AN:

78146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5432

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

994358

Other (OTH)

AF:

0.0000182

AC:

AN:

54924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.38_40+3del, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the TNNI3K protein (Splice site). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. This variant is also known as c.38_40+3del. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=17/183

disease causing

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over