rs1514176

Variant names:

• chr1-74525912-G-A
• rs1514176
• NM_015978.3:c.2352-14322G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015978.3(TNNI3K):​c.2352-14322G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 152,026 control chromosomes in the GnomAD database, including 18,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (18057 hom., cov: 32)
• Consequence: TNNI3K NM_015978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 18 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]

LRRC53 (HGNC:25255): (leucine rich repeat containing 53) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.2352-14322G>A		intron_variant	Intron 23 of 24	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.2655-14322G>A		intron_variant	Intron 25 of 26		NP_001106279.3
LRRC53	XM_017003081.2	c.49+10892C>T		intron_variant	Intron 1 of 3		XP_016858570.1
LRRC53	XM_011542512.4	c.49+10892C>T		intron_variant	Intron 1 of 2		XP_011540814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3K	ENST00000326637.8	c.2352-14322G>A		intron_variant	Intron 23 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.2655-14322G>A		intron_variant	Intron 25 of 26	2		ENSP00000450895.3
FPGT-TNNI3K	ENST00000648585.1	n.*2258-14322G>A		intron_variant	Intron 28 of 29			ENSP00000497631.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71894 AN: 151908 Hom.: 18052 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.513

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

GnomAD4 genome AF: 0.473 AC: 71910 AN: 152026 Hom.: 18057 Cov.: 32 AF XY: 0.467 AC XY: 34707 AN XY: 74294

African (AFR) AF: 0.317 AC: 13143 AN: 41450

American (AMR) AF: 0.451 AC: 6889 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2140 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1259 AN: 5176

South Asian (SAS) AF: 0.465 AC: 2236 AN: 4808

European-Finnish (FIN) AF: 0.517 AC: 5455 AN: 10546

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38966 AN: 67966

Other (OTH) AF: 0.512 AC: 1084 AN: 2116

Alfa AF: 0.536 Hom.: 30028

Bravo AF: 0.458

Asia WGS AF: 0.397 AC: 1383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.73
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

dbSNP: rs1514176; hg19: chr1-74991596;