rs505508

Variant names:

• chr1-74235611-T-A
• rs505508
• NM_015978.3:c.40+120T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-74235611-T-A
• chr1-74235611-T-C
• chr1-74235611-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015978.3(TNNI3K):​c.40+120T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 543,176 control chromosomes in the GnomAD database, including 267,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72831 hom., cov: 31)
  • Exomes 𝑓: 1.0 (194934 hom.)
• Consequence: TNNI3K NM_015978.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-74235611-T-A is Benign according to our data. Variant chr1-74235611-T-A is described in ClinVar as [Benign]. Clinvar id is 1273965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.40+120T>A		intron_variant	Intron 1 of 24	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.344-491T>A		intron_variant	Intron 3 of 26		NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.344-491T>A		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.40+120T>A		intron_variant	Intron 1 of 24	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.344-491T>A		intron_variant	Intron 3 of 26	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148419 AN: 151528 Hom.: 72770 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD4 exome AF: 0.998 AC: 390676 AN: 391530 Hom.: 194934 AF XY: 0.998 AC XY: 206489 AN XY: 206858

African (AFR) AF: 0.933 AC: 8551 AN: 9164

American (AMR) AF: 0.995 AC: 15153 AN: 15224

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 11296 AN: 11296

East Asian (EAS) AF: 1.00 AC: 26434 AN: 26434

South Asian (SAS) AF: 1.00 AC: 23896 AN: 23898

European-Finnish (FIN) AF: 1.00 AC: 40638 AN: 40638

Middle Eastern (MID) AF: 0.997 AC: 2036 AN: 2042

European-Non Finnish (NFE) AF: 1.00 AC: 240965 AN: 240996

Other (OTH) AF: 0.994 AC: 21707 AN: 21838

GnomAD4 genome AF: 0.980 AC: 148539 AN: 151646 Hom.: 72831 Cov.: 31 AF XY: 0.980 AC XY: 72641 AN XY: 74122

African (AFR) AF: 0.929 AC: 38530 AN: 41478

American (AMR) AF: 0.993 AC: 15060 AN: 15162

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3460 AN: 3460

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10592 AN: 10592

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67648 AN: 67664

Other (OTH) AF: 0.980 AC: 2059 AN: 2100

Alfa AF: 0.988 Hom.: 9218

Bravo AF: 0.976

Asia WGS AF: 0.996 AC: 3455 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.37
PhyloP100		-1.0
PromoterAI		-0.0040	Neutral
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: rs505508; hg19: chr1-74701295;