rs112562759

Variant names:

• chr19-55147019-T-C
• rs112562759
• NM_003283.6:c.35A>G

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.35A>G​(p.Glu12Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,611,034 control chromosomes in the GnomAD database, including 7,012 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.067 (469 hom., cov: 32)
  • Exomes 𝑓: 0.091 (6543 hom.)
• Consequence: TNNT1 NM_003283.6 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.53
• Publications: 6 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 (MetaRNN=0.0018885136).
• BP6: Variant 19-55147019-T-C is Benign according to our data. Variant chr19-55147019-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0998 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.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 14	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 13	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.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 14	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 14	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.35A>G	p.Glu12Gly	missense splice_region	Exon 3 of 13	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10139 AN: 152062 Hom.: 470 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0511

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.0692 AC: 16875 AN: 243906 AF XY: 0.0703

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.0366

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.0994

Gnomad OTH exome AF: 0.0796

GnomAD4 exome AF: 0.0908 AC: 132530 AN: 1458852 Hom.: 6543 Cov.: 33 AF XY: 0.0896 AC XY: 64977 AN XY: 725376

African (AFR) AF: 0.0157 AC: 525 AN: 33450

American (AMR) AF: 0.0384 AC: 1703 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.0951 AC: 2466 AN: 25940

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39662

South Asian (SAS) AF: 0.0377 AC: 3227 AN: 85502

European-Finnish (FIN) AF: 0.103 AC: 5494 AN: 53266

Middle Eastern (MID) AF: 0.0791 AC: 440 AN: 5566

European-Non Finnish (NFE) AF: 0.102 AC: 113391 AN: 1110770

Other (OTH) AF: 0.0875 AC: 5277 AN: 60294

GnomAD4 genome AF: 0.0666 AC: 10136 AN: 152182 Hom.: 469 Cov.: 32 AF XY: 0.0647 AC XY: 4816 AN XY: 74424

African (AFR) AF: 0.0162 AC: 674 AN: 41530

American (AMR) AF: 0.0509 AC: 779 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3472

East Asian (EAS) AF: 0.000970 AC: 5 AN: 5154

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4828

European-Finnish (FIN) AF: 0.0983 AC: 1042 AN: 10598

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6918 AN: 67984

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0907 Hom.: 320

Bravo AF: 0.0602

TwinsUK AF: 0.102 AC: 380

ALSPAC AF: 0.0916 AC: 353

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.0977 AC: 840

ExAC AF: 0.0697 AC: 8464

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0019	T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.080	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.020	B
Vest4		0.43
MPC		0.67
ClinPred		0.014	T
GERP RS		2.1
PromoterAI		-0.048	Neutral
Varity_R		0.17
gMVP		0.27
Mutation Taster		=92/8	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: rs112562759; hg19: chr19-55658387; COSMIC: COSV52572130; COSMIC: COSV52572130;