chr1-74236094-T-C

Variant names:

• chr1-74236094-T-C
• NM_015978.3:c.41-8T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015978.3(TNNI3K):​c.41-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNI3K NM_015978.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006594
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.725
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-74236094-T-C is Benign according to our data. Variant chr1-74236094-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3663274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.41-8T>C		splice_region_variant, intron_variant	Intron 1 of 24	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.344-8T>C		splice_region_variant, intron_variant	Intron 3 of 26		NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.344-8T>C		splice_region_variant, intron_variant	Intron 3 of 23		NP_001186256.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3K	ENST00000326637.8	c.41-8T>C		splice_region_variant, intron_variant	Intron 1 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.344-8T>C		splice_region_variant, intron_variant	Intron 3 of 26	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.80
PhyloP100		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr1-74701778;