rs11669534

Variant names:

• chr19-55146720-G-A
• rs11669534
• NM_003283.6:c.47-13C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-55146720-G-A
• chr19-55146720-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003283.6(TNNT1):​c.47-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,499,846 control chromosomes in the GnomAD database, including 20,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1416 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19302 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.0470
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-55146720-G-A is Benign according to our data. Variant chr19-55146720-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

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.47-13C>T		intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.47-13C>T		intron	N/A	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.47-13C>T		intron	N/A	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.47-13C>T		intron	N/A	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.47-13C>T		intron	N/A	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.47-13C>T		intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17915 AN: 151942 Hom.: 1414 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00291

Gnomad SAS AF: 0.0503

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.105 AC: 12796 AN: 121404 AF XY: 0.106

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.161 AC: 216723 AN: 1347786 Hom.: 19302 Cov.: 32 AF XY: 0.158 AC XY: 104449 AN XY: 659544

African (AFR) AF: 0.0250 AC: 767 AN: 30668

American (AMR) AF: 0.105 AC: 2990 AN: 28592

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3025 AN: 20652

East Asian (EAS) AF: 0.000560 AC: 21 AN: 37478

South Asian (SAS) AF: 0.0572 AC: 3960 AN: 69208

European-Finnish (FIN) AF: 0.136 AC: 6288 AN: 46070

Middle Eastern (MID) AF: 0.0874 AC: 449 AN: 5136

European-Non Finnish (NFE) AF: 0.182 AC: 191443 AN: 1054310

Other (OTH) AF: 0.140 AC: 7780 AN: 55672

GnomAD4 genome AF: 0.118 AC: 17918 AN: 152060 Hom.: 1416 Cov.: 31 AF XY: 0.114 AC XY: 8497 AN XY: 74350

African (AFR) AF: 0.0324 AC: 1344 AN: 41532

American (AMR) AF: 0.119 AC: 1817 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 466 AN: 3462

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5150

South Asian (SAS) AF: 0.0508 AC: 245 AN: 4824

European-Finnish (FIN) AF: 0.146 AC: 1546 AN: 10602

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12129 AN: 67888

Other (OTH) AF: 0.102 AC: 216 AN: 2112

Alfa AF: 0.0897 Hom.: 191

Bravo AF: 0.114

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 5 (3)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.047
PromoterAI		0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism (auto)

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: rs11669534; hg19: chr19-55658088;