19-55146635-GC-GCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_003283.6(TNNT1):c.73+45dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 479,704 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 31)

Exomes 𝑓: 0.012 ( 20 hom. )

Consequence

TNNT1
NM_003283.6 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.353

Publications

0 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 -10 ACMG points.

BP6

Variant 19-55146635-G-GC is Benign according to our data. Variant chr19-55146635-G-GC is described in ClinVar as Likely_benign. ClinVar VariationId is 259032.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0121 (4090/338640) while in subpopulation NFE AF = 0.016 (3811/237660). AF 95% confidence interval is 0.0156. There are 20 homozygotes in GnomAdExome4. There are 1943 alleles in the male GnomAdExome4 subpopulation. Median coverage is 15. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 AR,AD gene

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.73+45dupG	intron	N/A	NP_003274.3
TNNT1	NM_001126132.3		c.73+45dupG	intron	N/A	NP_001119604.1	P13805-3
TNNT1	NM_001126133.3		c.73+45dupG	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.73+45_73+46insG	intron	N/A	ENSP00000467176.1	P13805-1
TNNT1	ENST00000291901.12	TSL:1	c.73+45_73+46insG	intron	N/A	ENSP00000291901.8	P13805-3
TNNT1	ENST00000356783.9	TSL:1	c.73+45_73+46insG	intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

384

AN:

140936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000993

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000629

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000236

Gnomad SAS

AF:

0.000522

Gnomad FIN

AF:

0.000665

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00358

GnomAD2 exomes

AF:

0.00288

AC:

101

AN:

35046

AF XY:

0.00271

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.00149

Gnomad ASJ exome

AF:

0.000919

Gnomad EAS exome

AF:

0.000273

Gnomad FIN exome

AF:

0.000617

Gnomad NFE exome

AF:

0.00747

Gnomad OTH exome

AF:

0.00190

GnomAD4 exome

AF:

0.0121

AC:

4090

AN:

338640

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

1943

AN XY:

174202

show subpopulations

African (AFR)

AF:

0.00424

AC:

AN:

6370

American (AMR)

AF:

0.00195

AC:

AN:

10274

Ashkenazi Jewish (ASJ)

AF:

0.000621

AC:

AN:

6440

East Asian (EAS)

AF:

0.00172

AC:

AN:

6408

South Asian (SAS)

AF:

0.000338

AC:

AN:

38442

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

17118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

976

European-Non Finnish (NFE)

AF:

0.0160

AC:

3811

AN:

237660

Other (OTH)

AF:

0.0112

AC:

167

AN:

14952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<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:

0.00272

AC:

384

AN:

141064

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

175

AN XY:

68642

show subpopulations

African (AFR)

AF:

0.000990

AC:

AN:

39382

American (AMR)

AF:

0.000628

AC:

AN:

14334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3280

East Asian (EAS)

AF:

0.000236

AC:

AN:

4234

South Asian (SAS)

AF:

0.000521

AC:

AN:

3842

European-Finnish (FIN)

AF:

0.000665

AC:

AN:

9024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00501

AC:

320

AN:

63844

Other (OTH)

AF:

0.00354

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00125

Hom.:

Bravo

AF:

0.00258

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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