19-55141344-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003283.6(TNNT1):c.193-42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,498,868 control chromosomes in the GnomAD database, including 1,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 98 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1144 hom. )

Consequence

TNNT1
NM_003283.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0950

Publications

3 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 (BayesDel_noAF=-0.84).

BP6

Variant 19-55141344-G-C is Benign according to our data. Variant chr19-55141344-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 259030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0337 (5138/152288) while in subpopulation NFE AF = 0.0419 (2850/68012). AF 95% confidence interval is 0.0406. There are 98 homozygotes in GnomAd4. There are 2537 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 98 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.193-42C>G		intron_variant	Intron 7 of 13	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.193-42C>G		intron_variant	Intron 7 of 13	1	NM_003283.6	ENSP00000467176.1		P13805-1

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5140

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.0877

Gnomad AMR

AF:

0.0358

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0419

Gnomad OTH

AF:

0.0415

GnomAD2 exomes

AF:

0.0332

AC:

8310

AN:

250398

AF XY:

0.0335

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.0218

Gnomad ASJ exome

AF:

0.0414

Gnomad EAS exome

AF:

0.0168

Gnomad FIN exome

AF:

0.0402

Gnomad NFE exome

AF:

0.0441

Gnomad OTH exome

AF:

0.0401

GnomAD4 exome

AF:

0.0396

AC:

53320

AN:

1346580

Hom.:

1144

Cov.:

AF XY:

0.0390

AC XY:

26400

AN XY:

676308

show subpopulations

African (AFR)

AF:

0.0207

AC:

645

AN:

31204

American (AMR)

AF:

0.0220

AC:

982

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.0399

AC:

1012

AN:

25352

East Asian (EAS)

AF:

0.0229

AC:

898

AN:

39140

South Asian (SAS)

AF:

0.0160

AC:

1344

AN:

83918

European-Finnish (FIN)

AF:

0.0399

AC:

2116

AN:

53014

Middle Eastern (MID)

AF:

0.0527

AC:

292

AN:

5540

European-Non Finnish (NFE)

AF:

0.0435

AC:

43843

AN:

1007242

Other (OTH)

AF:

0.0386

AC:

2188

AN:

56624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2460

4921

7381

9842

12302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0337

AC:

5138

AN:

152288

Hom.:

Cov.:

AF XY:

0.0341

AC XY:

2537

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0190

AC:

788

AN:

41570

American (AMR)

AF:

0.0357

AC:

547

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3470

East Asian (EAS)

AF:

0.0180

AC:

AN:

5176

South Asian (SAS)

AF:

0.0137

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0433

AC:

459

AN:

10610

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0419

AC:

2850

AN:

68012

Other (OTH)

AF:

0.0411

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

268

536

805

1073

1341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0385

Hom.:

Bravo

AF:

0.0326

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Likely 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.84

CADD

Benign

0.030

(source)

DANN

Benign

0.46

PhyloP100

-0.095

PromoterAI

-0.015

Neutral

(source)

Mutation Taster

=100/0

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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19-55141344-G-C

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