NM_003283.6:c.751-16T>C

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.751-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,612,642 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (β˜…β˜…).

Frequency

Genomes: 𝑓 0.034 ( 276 hom., cov: 30)
Exomes 𝑓: 0.0033 ( 240 hom. )

Consequence

TNNT1
NM_003283.6 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.446

Publications

1 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)

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=-0.91).
BP6
Variant 19-55133943-A-G is Benign according to our data. Variant chr19-55133943-A-G is described in ClinVar as [Benign]. Clinvar id is 259033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNT1NM_003283.6 linkc.751-16T>C intron_variant Intron 12 of 13 ENST00000588981.6 NP_003274.3 P13805-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNT1ENST00000588981.6 linkc.751-16T>C intron_variant Intron 12 of 13 1 NM_003283.6 ENSP00000467176.1 P13805-1

Frequencies

GnomAD3 genomes
AF:
0.0336
AC:
5079
AN:
151132
Hom.:
276
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0132
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.0240
GnomAD2 exomes
AF:
0.00871
AC:
2180
AN:
250312
AF XY:
0.00610
show subpopulations
Gnomad AFR exome
AF:
0.118
Gnomad AMR exome
AF:
0.00645
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.00377
GnomAD4 exome
AF:
0.00330
AC:
4827
AN:
1461398
Hom.:
240
Cov.:
33
AF XY:
0.00278
AC XY:
2024
AN XY:
726992
show subpopulations
African (AFR)
AF:
0.119
AC:
3983
AN:
33480
American (AMR)
AF:
0.00693
AC:
310
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000348
AC:
30
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52950
Middle Eastern (MID)
AF:
0.00191
AC:
11
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000459
AC:
51
AN:
1112000
Other (OTH)
AF:
0.00732
AC:
442
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
302
603
905
1206
1508
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
128
256
384
512
640
<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:
0.0337
AC:
5092
AN:
151244
Hom.:
276
Cov.:
30
AF XY:
0.0313
AC XY:
2314
AN XY:
73888
show subpopulations
African (AFR)
AF:
0.118
AC:
4827
AN:
40744
American (AMR)
AF:
0.0131
AC:
199
AN:
15178
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5116
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000221
AC:
15
AN:
68000
Other (OTH)
AF:
0.0237
AC:
50
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
237
474
712
949
1186
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
54
108
162
216
270
<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:
0.0177
Hom.:
20
Bravo
AF:
0.0384
Asia WGS
AF:
0.00577
AC:
20
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 25, 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. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nemaline myopathy 5 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
0.81
DANN
Benign
0.37
PhyloP100
-0.45
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs77273500; hg19: chr19-55645311; API