rs965912

Variant names:

• chr11-1922972-A-G
• rs965912
• NM_006757.4:c.18-76A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-1922972-A-G
• chr11-1922972-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006757.4(TNNT3):​c.18-76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.798 in 1,613,150 control chromosomes in the GnomAD database, including 516,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43236 hom., cov: 32)
  • Exomes 𝑓: 0.80 (473669 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -2.20
• Publications: 12 publications found

Genes affected

TNNT3 (HGNC:11950): (troponin T3, fast skeletal type) The binding of Ca(2+) to the trimeric troponin complex initiates the process of muscle contraction. Increased Ca(2+) concentrations produce a conformational change in the troponin complex that is transmitted to tropomyosin dimers situated along actin filaments. The altered conformation permits increased interaction between a myosin head and an actin filament which, ultimately, produces a muscle contraction. The troponin complex has protein subunits C, I, and T. Subunit C binds Ca(2+) and subunit I binds to actin and inhibits actin-myosin interaction. Subunit T binds the troponin complex to the tropomyosin complex and is also required for Ca(2+)-mediated activation of actomyosin ATPase activity. There are 3 different troponin T genes that encode tissue-specific isoforms of subunit T for fast skeletal-, slow skeletal-, and cardiac-muscle. This gene encodes fast skeletal troponin T protein; also known as troponin T type 3. Alternative splicing results in multiple transcript variants encoding additional distinct troponin T type 3 isoforms. A developmentally regulated switch between fetal/neonatal and adult troponin T type 3 isoforms occurs. Additional splice variants have been described but their biological validity has not been established. Mutations in this gene may cause distal arthrogryposis multiplex congenita type 2B (DA2B). [provided by RefSeq, Oct 2009]

TNNT3 Gene-Disease associations (from GenCC):

• arthrogryposis, distal, type 2B2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia
• distal arthrogryposis type 2B1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: STRONG Submitted by: G2P
• nemaline myopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-1922972-A-G is Benign according to our data. Variant chr11-1922972-A-G is described in ClinVar as Benign. ClinVar VariationId is 31868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006757.4. 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
	TNNT3	NM_006757.4	MANE Select	c.18-76A>G		intron	N/A	NP_006748.1	P45378-2
	TNNT3	NM_001367846.1		c.18-76A>G		intron	N/A	NP_001354775.1	P45378-1
	TNNT3	NM_001363561.2		c.18-76A>G		intron	N/A	NP_001350490.1	P45378-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.18-76A>G		intron	N/A	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.18-76A>G		intron	N/A	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.18-76A>G		intron	N/A	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113028 AN: 151922 Hom.: 43225 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.771

GnomAD4 exome AF: 0.803 AC: 1173479 AN: 1461110 Hom.: 473669 Cov.: 49 AF XY: 0.807 AC XY: 586961 AN XY: 726890

African (AFR) AF: 0.542 AC: 18138 AN: 33478

American (AMR) AF: 0.879 AC: 39298 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 22274 AN: 26134

East Asian (EAS) AF: 0.928 AC: 36859 AN: 39698

South Asian (SAS) AF: 0.912 AC: 78668 AN: 86254

European-Finnish (FIN) AF: 0.766 AC: 40574 AN: 52940

Middle Eastern (MID) AF: 0.872 AC: 5032 AN: 5768

European-Non Finnish (NFE) AF: 0.795 AC: 884105 AN: 1111736

Other (OTH) AF: 0.804 AC: 48531 AN: 60380

GnomAD4 genome AF: 0.744 AC: 113084 AN: 152040 Hom.: 43236 Cov.: 32 AF XY: 0.748 AC XY: 55611 AN XY: 74316

African (AFR) AF: 0.554 AC: 22921 AN: 41410

American (AMR) AF: 0.834 AC: 12751 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2978 AN: 3472

East Asian (EAS) AF: 0.927 AC: 4782 AN: 5158

South Asian (SAS) AF: 0.915 AC: 4410 AN: 4822

European-Finnish (FIN) AF: 0.766 AC: 8116 AN: 10598

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.802 AC: 54518 AN: 67970

Other (OTH) AF: 0.767 AC: 1618 AN: 2110

Alfa AF: 0.786 Hom.: 39132

Bravo AF: 0.737

Asia WGS AF: 0.854 AC: 2968 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Arthrogryposis, distal, type 2B2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.54
DANN	Benign	0.54
PhyloP100		-2.2
PromoterAI		0.038	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: rs965912; hg19: chr11-1944202; COSMIC: COSV53484474; COSMIC: COSV53484474;