1-74369495-GT-AC

Variant names:

• chr1-74369495-GT-AC
• NM_015978.3:c.1577_1578delGTinsAC
• TNNI3K p.Gly526Asp

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_015978.3(TNNI3K):​c.1577_1578delGTinsAC​(p.Gly526Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNI3K NM_015978.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.43
• Publications: 0 publications found

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]

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]

ENSG00000237324 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_015978.3 (TNNI3K) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3K	NM_015978.3	MANE Select	c.1577_1578delGTinsAC	p.Gly526Asp	missense	N/A	NP_057062.1	Q59H18-2
	FPGT-TNNI3K	NM_001112808.3		c.1880_1881delGTinsAC	p.Gly627Asp	missense	N/A	NP_001106279.3
	FPGT-TNNI3K	NM_001199327.2		c.1880_1881delGTinsAC	p.Gly627Asp	missense	N/A	NP_001186256.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3K	ENST00000326637.8	TSL:1 MANE Select	c.1577_1578delGTinsAC	p.Gly526Asp	missense	N/A	ENSP00000322251.3	Q59H18-2
	FPGT-TNNI3K	ENST00000557284.7	TSL:2	c.1880_1881delGTinsAC	p.Gly627Asp	missense	N/A	ENSP00000450895.3
	FPGT-TNNI3K	ENST00000370899.7	TSL:2	c.1880_1881delGTinsAC	p.Gly627Asp	missense	N/A	ENSP00000359936.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-74835179;