NM_003283.6:c.33-8G>A

Variant names:

• chr19-55147029-C-T
• rs76630067
• NM_003283.6:c.33-8G>A

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.33-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,611,684 control chromosomes in the GnomAD database, including 1,349 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (237 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1112 hom.)
• Consequence: TNNT1 NM_003283.6 splice_region, intron
• Scores: Splicing: ADA: 0.05309
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.728
• Publications: 3 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-55147029-C-T is Benign according to our data. Variant chr19-55147029-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 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.33-8G>A		splice_region intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.33-8G>A		splice_region intron	N/A	NP_001119604.1
	TNNT1	NM_001126133.3		c.33-8G>A		splice_region 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.33-8G>A		splice_region intron	N/A	ENSP00000467176.1
	TNNT1	ENST00000291901.12	TSL:1	c.33-8G>A		splice_region intron	N/A	ENSP00000291901.8
	TNNT1	ENST00000356783.9	TSL:1	c.33-8G>A		splice_region intron	N/A	ENSP00000349233.4

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6946 AN: 152108 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0482 AC: 11786 AN: 244394 AF XY: 0.0450

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0299 AC: 43608 AN: 1459458 Hom.: 1112 Cov.: 34 AF XY: 0.0299 AC XY: 21710 AN XY: 725772

African (AFR) AF: 0.0752 AC: 2518 AN: 33462

American (AMR) AF: 0.0997 AC: 4421 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00955 AC: 248 AN: 25974

East Asian (EAS) AF: 0.118 AC: 4688 AN: 39646

South Asian (SAS) AF: 0.0531 AC: 4545 AN: 85602

European-Finnish (FIN) AF: 0.0301 AC: 1605 AN: 53320

Middle Eastern (MID) AF: 0.00745 AC: 42 AN: 5634

European-Non Finnish (NFE) AF: 0.0212 AC: 23595 AN: 1111206

Other (OTH) AF: 0.0323 AC: 1946 AN: 60288

GnomAD4 genome AF: 0.0457 AC: 6962 AN: 152226 Hom.: 237 Cov.: 32 AF XY: 0.0483 AC XY: 3595 AN XY: 74432

African (AFR) AF: 0.0705 AC: 2928 AN: 41546

American (AMR) AF: 0.0821 AC: 1256 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.108 AC: 559 AN: 5154

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4826

European-Finnish (FIN) AF: 0.0347 AC: 368 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1443 AN: 67998

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0231 Hom.: 39

Bravo AF: 0.0510

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Nemaline myopathy 5 (2)
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Nemaline Myopathy, Recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.84
PhyloP100		-0.73
BranchPoint Hunter		1.0
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.053
dbscSNV1_RF	Benign	0.088
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: rs76630067; hg19: chr19-55658397; COSMIC: COSV107342885; COSMIC: COSV107342885;