chr1-74235967-A-T

Variant names:

• chr1-74235967-A-T
• rs500203
• NM_015978.3:c.41-135A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015978.3(TNNI3K):​c.41-135A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 547,348 control chromosomes in the GnomAD database, including 52,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12014 hom., cov: 32)
  • Exomes 𝑓: 0.44 (40849 hom.)
• Consequence: TNNI3K NM_015978.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.333
• Publications: 8 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-74235967-A-T is Benign according to our data. Variant chr1-74235967-A-T is described in ClinVar as [Benign]. Clinvar id is 1258735.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.41-135A>T		intron_variant	Intron 1 of 24	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.344-135A>T		intron_variant	Intron 3 of 26		NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.344-135A>T		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.41-135A>T		intron_variant	Intron 1 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.344-135A>T		intron_variant	Intron 3 of 26	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57252 AN: 151232 Hom.: 12022 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.445 AC: 176168 AN: 396000 Hom.: 40849 AF XY: 0.448 AC XY: 92413 AN XY: 206152

African (AFR) AF: 0.202 AC: 1813 AN: 8996

American (AMR) AF: 0.397 AC: 3909 AN: 9854

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 5638 AN: 10776

East Asian (EAS) AF: 0.687 AC: 15903 AN: 23146

South Asian (SAS) AF: 0.522 AC: 14989 AN: 28688

European-Finnish (FIN) AF: 0.442 AC: 15524 AN: 35092

Middle Eastern (MID) AF: 0.479 AC: 768 AN: 1604

European-Non Finnish (NFE) AF: 0.422 AC: 108380 AN: 256694

Other (OTH) AF: 0.437 AC: 9244 AN: 21150

GnomAD4 genome AF: 0.378 AC: 57252 AN: 151348 Hom.: 12014 Cov.: 32 AF XY: 0.385 AC XY: 28493 AN XY: 73956

African (AFR) AF: 0.201 AC: 8318 AN: 41412

American (AMR) AF: 0.403 AC: 6109 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1865 AN: 3462

East Asian (EAS) AF: 0.728 AC: 3758 AN: 5162

South Asian (SAS) AF: 0.509 AC: 2450 AN: 4816

European-Finnish (FIN) AF: 0.466 AC: 4891 AN: 10498

Middle Eastern (MID) AF: 0.415 AC: 118 AN: 284

European-Non Finnish (NFE) AF: 0.421 AC: 28418 AN: 67554

Other (OTH) AF: 0.381 AC: 799 AN: 2098

Alfa AF: 0.384 Hom.: 1633

Bravo AF: 0.368

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2019

GeneDx

Significance: 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	-0.67
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		0.33
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: rs500203; hg19: chr1-74701651;