NM_003283.6:c.*110T>C

Variant names:

• chr19-55132805-A-G
• rs147109223
• NM_003283.6:c.*110T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003283.6(TNNT1):​c.*110T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,041,460 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: TNNT1 NM_003283.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	NM_003283.6	MANE Select	c.*110T>C		3_prime_UTR	Exon 14 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.*110T>C		3_prime_UTR	Exon 14 of 14	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.*110T>C		3_prime_UTR	Exon 13 of 13	NP_001119605.1	P13805-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.*110T>C		3_prime_UTR	Exon 14 of 14	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.*110T>C		3_prime_UTR	Exon 14 of 14	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.*110T>C		3_prime_UTR	Exon 13 of 13	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152188 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000307 AC: 273 AN: 889154 Hom.: 4 Cov.: 12 AF XY: 0.000243 AC XY: 111 AN XY: 457126

African (AFR) AF: 0.00948 AC: 206 AN: 21720

American (AMR) AF: 0.000402 AC: 14 AN: 34806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21912

East Asian (EAS) AF: 0.0000299 AC: 1 AN: 33404

South Asian (SAS) AF: 0.00 AC: 0 AN: 68998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47694

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4718

European-Non Finnish (NFE) AF: 0.0000293 AC: 18 AN: 614526

Other (OTH) AF: 0.000798 AC: 33 AN: 41376

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152306 Hom.: 2 Cov.: 31 AF XY: 0.00274 AC XY: 204 AN XY: 74472

African (AFR) AF: 0.0100 AC: 417 AN: 41574

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00308

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nemaline myopathy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.58
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147109223; hg19: chr19-55644173;