Genetic Variant NM_003283.6:c.816C>A (chr19-55132936-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_003283.6(TNNT1):c.816C>A(p.Arg272Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R272R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNNT1
NM_003283.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.37

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, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP7

Synonymous conserved (PhyloP=-3.37 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.816C>A	p.Arg272Arg	synonymous_variant	Exon 14 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.816C>A	p.Arg272Arg	synonymous_variant	Exon 14 of 14	1	NM_003283.6	ENSP00000467176.1		P13805-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451628

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

43120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25764

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.00

AC:

AN:

83790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108392

Other (OTH)

AF:

0.00

AC:

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.66

(source)

DANN

Benign

0.89

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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NM_003283.6:c.816C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over