NM_003283.6:c.128+17T>G

Variant names:

• chr19-55145527-A-C
• rs201135309
• NM_003283.6:c.128+17T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003283.6(TNNT1):​c.128+17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,430 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.442
• 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, 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-55145527-A-C is Benign according to our data. Variant chr19-55145527-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 259029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 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.128+17T>G		intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.128+17T>G		intron	N/A	NP_001119604.1
	TNNT1	NM_001126133.3		c.95+17T>G		intron	N/A	NP_001119605.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.128+17T>G		intron	N/A	ENSP00000467176.1
	TNNT1	ENST00000291901.12	TSL:1	c.128+17T>G		intron	N/A	ENSP00000291901.8
	TNNT1	ENST00000356783.9	TSL:1	c.95+17T>G		intron	N/A	ENSP00000349233.4

Frequencies

GnomAD3 genomes AF: 0.000980 AC: 149 AN: 152038 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000833 AC: 209 AN: 250992 AF XY: 0.000833

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00168 AC: 2451 AN: 1461274 Hom.: 2 Cov.: 31 AF XY: 0.00155 AC XY: 1129 AN XY: 726966

African (AFR) AF: 0.000388 AC: 13 AN: 33464

American (AMR) AF: 0.000828 AC: 37 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86236

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00203 AC: 2260 AN: 1111584

Other (OTH) AF: 0.00186 AC: 112 AN: 60358

GnomAD4 genome AF: 0.000979 AC: 149 AN: 152156 Hom.: 0 Cov.: 30 AF XY: 0.000954 AC XY: 71 AN XY: 74400

African (AFR) AF: 0.000410 AC: 17 AN: 41500

American (AMR) AF: 0.00183 AC: 28 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 67986

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000940 Hom.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Nemaline myopathy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.65
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201135309; hg19: chr19-55656895;