rs112562759

Positions:

chr19-55147019-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003283.6(TNNT1):c.35A>G(p.Glu12Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,611,034 control chromosomes in the GnomAD database, including 7,012 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 469 hom., cov: 32)

Exomes 𝑓: 0.091 ( 6543 hom. )

Consequence

TNNT1
NM_003283.6 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018885136).

BP6

Variant 19-55147019-T-C is Benign according to our data. Variant chr19-55147019-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 31865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55147019-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0998 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6 linkuse as main transcript	c.35A>G	p.Glu12Gly	missense_variant, splice_region_variant	3/14	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6 linkuse as main transcript	c.35A>G	p.Glu12Gly	missense_variant, splice_region_variant	3/14	1	NM_003283.6	ENSP00000467176		P13805-1

Frequencies

GnomAD3 genomes

AF:

0.0667

AC:

10139

AN:

152062

Hom.:

470

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0511

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.0983

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0750

GnomAD3 exomes

AF:

0.0692

AC:

16875

AN:

243906

Hom.:

753

AF XY:

0.0703

AC XY:

9262

AN XY:

131802

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.0914

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.0359

Gnomad FIN exome

AF:

0.0991

Gnomad NFE exome

AF:

0.0994

Gnomad OTH exome

AF:

0.0796

GnomAD4 exome

AF:

0.0908

AC:

132530

AN:

1458852

Hom.:

6543

Cov.:

AF XY:

0.0896

AC XY:

64977

AN XY:

725376

show subpopulations

Gnomad4 AFR exome

AF:

0.0157

Gnomad4 AMR exome

AF:

0.0384

Gnomad4 ASJ exome

AF:

0.0951

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0377

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.0875

GnomAD4 genome

AF:

0.0666

AC:

10136

AN:

152182

Hom.:

469

Cov.:

AF XY:

0.0647

AC XY:

4816

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.0509

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.000970

Gnomad4 SAS

AF:

0.0346

Gnomad4 FIN

AF:

0.0983

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.0743

Alfa

AF:

0.0907

Hom.:

320

Bravo

AF:

0.0602

TwinsUK

AF:

0.102

AC:

380

ALSPAC

AF:

0.0916

AC:

353

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0977

AC:

840

ExAC

AF:

0.0697

AC:

8464

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Glu12Gly in exon 3 of TNNT1: This variant is not expected to have clinical sig nificance because it has been identified in 9.8% (840/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs112562759). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nemaline myopathy 5

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT1)	Mar 18, 2012	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial restrictive cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

.;.;.;D;.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.60

.;T;T;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

1.8

L;L;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;N

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

.;D;D;.;.;.;.

REVEL

Uncertain

0.42

Sift

Benign

0.080

.;T;D;.;.;.;.

Sift4G

Uncertain

0.0060

D;D;D;D;.;D;D

Polyphen

0.020

B;B;B;B;.;.;.

Vest4

0.43

MPC

0.67

ClinPred

0.014

GERP RS

2.1

Varity_R

0.17

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over