rs890868

Positions:

• chr19-55132957-C-A
• chr19-55132957-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003283.6(TNNT1):​c.795G>T​(p.Arg265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,601,424 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0045 (223 hom.)
• Consequence: TNNT1 NM_003283.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.333

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-55132957-C-A is Benign according to our data. Variant chr19-55132957-C-A is described in ClinVar as [Benign]. Clinvar id is 31857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.333 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT1	NM_003283.6	c.795G>T	p.Arg265=	synonymous_variant	14/14	ENST00000588981.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT1	ENST00000588981.6	c.795G>T	p.Arg265=	synonymous_variant	14/14	1	NM_003283.6

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1092 AN: 152166 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00453 AC: 6571 AN: 1449138 Hom.: 223 Cov.: 31 AF XY: 0.00423 AC XY: 3045 AN XY: 719514

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.0000777

Gnomad4 EAS exome AF: 0.0888

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00716 AC: 1090 AN: 152286 Hom.: 18 Cov.: 31 AF XY: 0.00902 AC XY: 672 AN XY: 74462

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0684

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00869

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT1)	Mar 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2019	- -

Nemaline myopathy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs890868; hg19: chr19-55644325;