rs67795913

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.129-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,310 control chromosomes in the GnomAD database, including 14,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 966 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13086 hom. )

Consequence

TNNT1
NM_003283.6 intron

Scores

Splicing: ADA: 0.8072

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.256

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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
nemaline myopathy 5B, autosomal recessive, childhood-onset
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
nemaline myopathy
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, 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 (BayesDel_noAF=-0.76).

BP6

Variant 19-55141929-A-C is Benign according to our data. Variant chr19-55141929-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003283.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNNT1	NM_003283.6	MANE Select	c.129-9T>G	intron	N/A	NP_003274.3
TNNT1	NM_001126132.3		c.129-9T>G	intron	N/A	NP_001119604.1	P13805-3
TNNT1	NM_001126133.3		c.96-9T>G	intron	N/A	NP_001119605.1	P13805-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.129-9T>G	intron	N/A	ENSP00000467176.1	P13805-1
TNNT1	ENST00000291901.12	TSL:1	c.129-9T>G	intron	N/A	ENSP00000291901.8	P13805-3
TNNT1	ENST00000356783.9	TSL:1	c.96-9T>G	intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15892

AN:

151960

Hom.:

966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.0845

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.120

AC:

30207

AN:

251244

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.0337

Gnomad AMR exome

AF:

0.0791

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.131

AC:

191240

AN:

1461232

Hom.:

13086

Cov.:

AF XY:

0.130

AC XY:

94420

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.0360

AC:

1206

AN:

33472

American (AMR)

AF:

0.0808

AC:

3612

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

3095

AN:

26130

East Asian (EAS)

AF:

0.193

AC:

7677

AN:

39682

South Asian (SAS)

AF:

0.0870

AC:

7507

AN:

86252

European-Finnish (FIN)

AF:

0.131

AC:

6983

AN:

53388

Middle Eastern (MID)

AF:

0.165

AC:

947

AN:

5742

European-Non Finnish (NFE)

AF:

0.137

AC:

152265

AN:

1111488

Other (OTH)

AF:

0.132

AC:

7948

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

8329

16658

24988

33317

41646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5412

10824

16236

21648

27060

<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:

0.104

AC:

15882

AN:

152078

Hom.:

966

Cov.:

AF XY:

0.105

AC XY:

7807

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0374

AC:

1552

AN:

41500

American (AMR)

AF:

0.102

AC:

1553

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

399

AN:

3468

East Asian (EAS)

AF:

0.183

AC:

943

AN:

5152

South Asian (SAS)

AF:

0.0844

AC:

406

AN:

4812

European-Finnish (FIN)

AF:

0.129

AC:

1366

AN:

10584

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9145

AN:

67970

Other (OTH)

AF:

0.125

AC:

265

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

721

1443

2164

2886

3607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.125

Hom.:

411

Bravo

AF:

0.102

Asia WGS

AF:

0.0980

AC:

341

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Nemaline myopathy 5 (4)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

-0.26

PromoterAI

-0.023

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: -9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over