chr19-55132755-G-C

Variant names:

• chr19-55132755-G-C
• rs10414711
• NM_003283.6:c.*160C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003283.6(TNNT1):​c.*160C>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 0.276 in 698,570 control chromosomes in the GnomAD database, including 28,041 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (5643 hom., cov: 31)
  • Exomes 𝑓: 0.28 (22398 hom.)
• Consequence: TNNT1 NM_003283.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 6 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, 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.*160C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.*160C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_003283.6	ENSP00000467176.1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41203 AN: 151962 Hom.: 5629 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.282

GnomAD4 exome AF: 0.277 AC: 151479 AN: 546488 Hom.: 22398 Cov.: 6 AF XY: 0.284 AC XY: 82362 AN XY: 289974

African (AFR) AF: 0.280 AC: 4080 AN: 14564

American (AMR) AF: 0.295 AC: 8129 AN: 27594

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 5173 AN: 17254

East Asian (EAS) AF: 0.367 AC: 11620 AN: 31622

South Asian (SAS) AF: 0.417 AC: 22994 AN: 55200

European-Finnish (FIN) AF: 0.294 AC: 12067 AN: 41096

Middle Eastern (MID) AF: 0.313 AC: 1217 AN: 3890

European-Non Finnish (NFE) AF: 0.240 AC: 78049 AN: 325782

Other (OTH) AF: 0.276 AC: 8150 AN: 29486

GnomAD4 genome AF: 0.271 AC: 41244 AN: 152082 Hom.: 5643 Cov.: 31 AF XY: 0.277 AC XY: 20587 AN XY: 74342

African (AFR) AF: 0.278 AC: 11519 AN: 41488

American (AMR) AF: 0.271 AC: 4144 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1032 AN: 3464

East Asian (EAS) AF: 0.362 AC: 1872 AN: 5174

South Asian (SAS) AF: 0.431 AC: 2076 AN: 4814

European-Finnish (FIN) AF: 0.296 AC: 3133 AN: 10588

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16549 AN: 67970

Other (OTH) AF: 0.282 AC: 596 AN: 2112

Alfa AF: 0.253 Hom.: 641

Bravo AF: 0.264

Asia WGS AF: 0.359 AC: 1246 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

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	-0.88
CADD	Benign	0.80
DANN	Benign	0.39
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10414711; hg19: chr19-55644123; COSMIC: COSV52570335;