19-55146713-G-C

Variant names:

• chr19-55146713-G-C
• rs375682055
• NM_003283.6:c.47-6C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003283.6(TNNT1):​c.47-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,509,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: TNNT1 NM_003283.6 splice_region, intron
• Scores: Splicing: ADA: 0.01587
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.460
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• nemaline myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• nemaline myopathy 5C, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-55146713-G-C is Benign according to our data. Variant chr19-55146713-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259031.

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.47-6C>G		splice_region intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.47-6C>G		splice_region intron	N/A	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.47-6C>G		splice_region 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.47-6C>G		splice_region intron	N/A	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.47-6C>G		splice_region intron	N/A	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.47-6C>G		splice_region intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 26 AN: 126842 AF XY: 0.000208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.000298

GnomAD4 exome AF: 0.000223 AC: 303 AN: 1356832 Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 153 AN XY: 664736

African (AFR) AF: 0.0000646 AC: 2 AN: 30974

American (AMR) AF: 0.00 AC: 0 AN: 30166

Ashkenazi Jewish (ASJ) AF: 0.00441 AC: 93 AN: 21106

East Asian (EAS) AF: 0.00 AC: 0 AN: 37392

South Asian (SAS) AF: 0.00 AC: 0 AN: 70404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5166

European-Non Finnish (NFE) AF: 0.000173 AC: 183 AN: 1059252

Other (OTH) AF: 0.000446 AC: 25 AN: 55994

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74412

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000609 Hom.: 3

Bravo AF: 0.000208

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.46
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.040		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: rs375682055; hg19: chr19-55658081;