1-74489172-C-CT

Position:

• chr1-74489172-C-CT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_015978.3(TNNI3K):​c.2122-11dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,601,692 control chromosomes in the GnomAD database, including 2,690 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.083 (1363 hom., cov: 31)
  • Exomes 𝑓: 0.020 (1327 hom.)
• Consequence: TNNI3K NM_015978.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.01

Genes affected

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]

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 1-74489172-C-CT is Benign according to our data. Variant chr1-74489172-C-CT is described in ClinVar as [Benign]. Clinvar id is 1603128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC53	NM_001382280.1	c.-26-5798_-26-5797insA		intron_variant		ENST00000294635.5
TNNI3K	NM_015978.3	c.2122-11dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000326637.8
FPGT-TNNI3K	NM_001112808.3	c.2425-11dup		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC53	ENST00000294635.5	c.-26-5798_-26-5797insA		intron_variant		5	NM_001382280.1	P1
TNNI3K	ENST00000326637.8	c.2122-11dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_015978.3	P1

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 12575 AN: 152018 Hom.: 1362 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0665

GnomAD3 exomes AF: 0.0287 AC: 6908 AN: 240924 Hom.: 541 AF XY: 0.0241 AC XY: 3140 AN XY: 130390

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0198 AC: 28694 AN: 1449556 Hom.: 1327 Cov.: 30 AF XY: 0.0189 AC XY: 13629 AN XY: 720844

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.00505

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0289

GnomAD4 genome AF: 0.0827 AC: 12580 AN: 152136 Hom.: 1363 Cov.: 31 AF XY: 0.0804 AC XY: 5978 AN XY: 74384

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.0384

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0445 Hom.: 112

Bravo AF: 0.0940

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs45592143; hg19: chr1-74954856;