rs112562759

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12Q) has been classified as Uncertain significance.

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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

nemaline myopathy 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
nemaline myopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
nemaline myopathy 5C, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TNNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 31865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.35A>G	p.Glu12Gly	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000588981.6	NP_003274.3	P13805-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6 link	c.35A>G	p.Glu12Gly	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_003283.6	ENSP00000467176.1		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

GnomAD2 exomes

AF:

0.0692

AC:

16875

AN:

243906

AF XY:

0.0703

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 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

African (AFR)

AF:

0.0157

AC:

525

AN:

33450

American (AMR)

AF:

0.0384

AC:

1703

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.0951

AC:

2466

AN:

25940

East Asian (EAS)

AF:

0.000176

AC:

AN:

39662

South Asian (SAS)

AF:

0.0377

AC:

3227

AN:

85502

European-Finnish (FIN)

AF:

0.103

AC:

5494

AN:

53266

Middle Eastern (MID)

AF:

0.0791

AC:

440

AN:

5566

European-Non Finnish (NFE)

AF:

0.102

AC:

113391

AN:

1110770

Other (OTH)

AF:

0.0875

AC:

5277

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

6814

13628

20441

27255

34069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4030

8060

12090

16120

20150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0666

AC:

10136

AN:

152182

Hom.:

469

Cov.:

AF XY:

0.0647

AC XY:

4816

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0162

AC:

674

AN:

41530

American (AMR)

AF:

0.0509

AC:

779

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

354

AN:

3472

East Asian (EAS)

AF:

0.000970

AC:

AN:

5154

South Asian (SAS)

AF:

0.0346

AC:

167

AN:

4828

European-Finnish (FIN)

AF:

0.0983

AC:

1042

AN:

10598

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6918

AN:

67984

Other (OTH)

AF:

0.0743

AC:

157

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

477

954

1430

1907

2384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Sep 14, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 10, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 5

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 18, 2012

Leiden Muscular Dystrophy (TNNT1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated Cardiomyopathy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial restrictive cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

2.5

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

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.17

gMVP

0.27

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over