rs73060953

Variant names:

• chr19-55141344-G-C
• rs73060953
• NM_003283.6:c.193-42C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-55141344-G-C
• chr19-55141344-G-A
• chr19-55141344-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003283.6(TNNT1):​c.193-42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,498,868 control chromosomes in the GnomAD database, including 1,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (98 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1144 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0950
• 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, 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=-0.84).
• BP6: Variant 19-55141344-G-C is Benign according to our data. Variant chr19-55141344-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0337 (5138/152288) while in subpopulation NFE AF = 0.0419 (2850/68012). AF 95% confidence interval is 0.0406. There are 98 homozygotes in GnomAd4. There are 2537 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 98 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.193-42C>G		intron	N/A	NP_003274.3
	TNNT1	NM_001126132.3		c.193-42C>G		intron	N/A	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.160-42C>G		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.193-42C>G		intron	N/A	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.193-42C>G		intron	N/A	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.160-42C>G		intron	N/A	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5140 AN: 152170 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0332 AC: 8310 AN: 250398 AF XY: 0.0335

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0414

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0401

GnomAD4 exome AF: 0.0396 AC: 53320 AN: 1346580 Hom.: 1144 Cov.: 21 AF XY: 0.0390 AC XY: 26400 AN XY: 676308

African (AFR) AF: 0.0207 AC: 645 AN: 31204

American (AMR) AF: 0.0220 AC: 982 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0399 AC: 1012 AN: 25352

East Asian (EAS) AF: 0.0229 AC: 898 AN: 39140

South Asian (SAS) AF: 0.0160 AC: 1344 AN: 83918

European-Finnish (FIN) AF: 0.0399 AC: 2116 AN: 53014

Middle Eastern (MID) AF: 0.0527 AC: 292 AN: 5540

European-Non Finnish (NFE) AF: 0.0435 AC: 43843 AN: 1007242

Other (OTH) AF: 0.0386 AC: 2188 AN: 56624

GnomAD4 genome AF: 0.0337 AC: 5138 AN: 152288 Hom.: 98 Cov.: 32 AF XY: 0.0341 AC XY: 2537 AN XY: 74476

African (AFR) AF: 0.0190 AC: 788 AN: 41570

American (AMR) AF: 0.0357 AC: 547 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.0180 AC: 93 AN: 5176

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4826

European-Finnish (FIN) AF: 0.0433 AC: 459 AN: 10610

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0419 AC: 2850 AN: 68012

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0385 Hom.: 28

Bravo AF: 0.0326

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.030
DANN	Benign	0.46
PhyloP100		-0.095
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	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: rs73060953; hg19: chr19-55652712;