rs77273500

Variant names:

• chr19-55133943-A-G
• rs77273500
• NM_003283.6:c.751-16T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-55133943-A-G
• chr19-55133943-A-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.751-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,612,642 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (276 hom., cov: 30)
  • Exomes 𝑓: 0.0033 (240 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.446
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• nemaline myopathy 5B, autosomal recessive, childhood-onset

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• nemaline myopathy

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-55133943-A-G is Benign according to our data. Variant chr19-55133943-A-G is described in ClinVar as Benign. ClinVar VariationId is 259033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 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.751-16T>C		intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.703-16T>C		intron	N/A	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.670-16T>C		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.751-16T>C		intron	N/A	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.703-16T>C		intron	N/A	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.670-16T>C		intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5079 AN: 151132 Hom.: 276 Cov.: 30

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.00871 AC: 2180 AN: 250312 AF XY: 0.00610

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00330 AC: 4827 AN: 1461398 Hom.: 240 Cov.: 33 AF XY: 0.00278 AC XY: 2024 AN XY: 726992

African (AFR) AF: 0.119 AC: 3983 AN: 33480

American (AMR) AF: 0.00693 AC: 310 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1112000

Other (OTH) AF: 0.00732 AC: 442 AN: 60386

GnomAD4 genome AF: 0.0337 AC: 5092 AN: 151244 Hom.: 276 Cov.: 30 AF XY: 0.0313 AC XY: 2314 AN XY: 73888

African (AFR) AF: 0.118 AC: 4827 AN: 40744

American (AMR) AF: 0.0131 AC: 199 AN: 15178

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68000

Other (OTH) AF: 0.0237 AC: 50 AN: 2108

Alfa AF: 0.0177 Hom.: 20

Bravo AF: 0.0384

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.81
DANN	Benign	0.37
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77273500;

hg19: chr19-55645311;