1-74489216-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015978.3(TNNI3K):c.2149A>G(p.Met717Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,612,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M717T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TNNI3K NM_015978.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.783

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:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013005018).
• BP6: Variant 1-74489216-A-G is Benign according to our data. Variant chr1-74489216-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 740641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-74489216-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000335 (51/152340) while in subpopulation AMR AF= 0.00183 (28/15300). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3K	NM_015978.3	c.2149A>G	p.Met717Val	missense_variant	22/25	ENST00000326637.8
FPGT-TNNI3K	NM_001112808.3	c.2452A>G	p.Met818Val	missense_variant	24/27
LRRC53	NM_001382280.1	c.-26-5841T>C		intron_variant		ENST00000294635.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3K	ENST00000326637.8	c.2149A>G	p.Met717Val	missense_variant	22/25	1	NM_015978.3	P1
LRRC53	ENST00000294635.5	c.-26-5841T>C		intron_variant		5	NM_001382280.1	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000393 AC: 98 AN: 249602 Hom.: 0 AF XY: 0.000304 AC XY: 41 AN XY: 134956

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000179 AC: 262 AN: 1460000 Hom.: 0 Cov.: 30 AF XY: 0.000169 AC XY: 123 AN XY: 726338

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74492

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000510

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

TNNI3K-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	1.2
Dann	Benign	0.60
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
REVEL	Benign	0.25
Sift4G	Benign	0.27	T;T
Polyphen		0.0	.;B
Vest4		0.27
MVP		0.57
MPC		0.023
ClinPred		0.0050	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144008222; hg19: chr1-74954900;