chr19-55132786-G-C

Variant names:

• chr19-55132786-G-C
• rs1014566207
• NM_003283.6:c.*129C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003283.6(TNNT1):​c.*129C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 855,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TNNT1 NM_003283.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.627
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*129C>G		3_prime_UTR	Exon 14 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.*129C>G		3_prime_UTR	Exon 14 of 14	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.*129C>G		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.*129C>G		3_prime_UTR	Exon 14 of 14	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000964355.1		c.*129C>G		3_prime_UTR	Exon 14 of 14	ENSP00000634414.1
	TNNT1	ENST00000291901.12	TSL:1	c.*129C>G		downstream_gene	N/A	ENSP00000291901.8	P13805-3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000995 AC: 7 AN: 703228 Hom.: 0 Cov.: 9 AF XY: 0.0000135 AC XY: 5 AN XY: 369404

African (AFR) AF: 0.000165 AC: 3 AN: 18130

American (AMR) AF: 0.00 AC: 0 AN: 33650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20318

East Asian (EAS) AF: 0.00 AC: 0 AN: 32518

South Asian (SAS) AF: 0.00 AC: 0 AN: 64552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4362

European-Non Finnish (NFE) AF: 0.00000447 AC: 2 AN: 447894

Other (OTH) AF: 0.0000570 AC: 2 AN: 35080

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

African (AFR) AF: 0.000145 AC: 6 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000604

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	-0.84
CADD	Benign	0.33
DANN	Benign	0.41
PhyloP100		-0.63

Splicing

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

Other links and lift over

dbSNP: rs1014566207; hg19: chr19-55644154;