rs77483833

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001267550.2(TTN):c.100766-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001820

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.467

Variant links:

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN links:

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-178535858-G-A is Benign according to our data. Variant chr2-178535858-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.100766-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5
TTN-AS1	NR_038272.1 linkuse as main transcript	n.316+30G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.100766-9C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.416+12222G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

199

AN:

104304

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00161

Gnomad AMI

AF:

0.00332

Gnomad AMR

AF:

0.000908

Gnomad ASJ

AF:

0.000754

Gnomad EAS

AF:

0.000521

Gnomad SAS

AF:

0.00170

Gnomad FIN

AF:

0.00969

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00155

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0116

AC:

643

AN:

55198

Hom.:

AF XY:

0.0115

AC XY:

336

AN XY:

29178

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00962

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.00803

Gnomad SAS exome

AF:

0.0121

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00813

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00220

AC:

2489

AN:

1129796

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1403

AN XY:

553568

show subpopulations

Gnomad4 AFR exome

AF:

0.00396

Gnomad4 AMR exome

AF:

0.00895

Gnomad4 ASJ exome

AF:

0.00303

Gnomad4 EAS exome

AF:

0.00344

Gnomad4 SAS exome

AF:

0.00938

Gnomad4 FIN exome

AF:

0.00579

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00163

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00192

AC:

200

AN:

104330

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

103

AN XY:

49684

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000907

Gnomad4 ASJ

AF:

0.000754

Gnomad4 EAS

AF:

0.000522

Gnomad4 SAS

AF:

0.00171

Gnomad4 FIN

AF:

0.00969

Gnomad4 NFE

AF:

0.00155

Gnomad4 OTH

AF:

0.000705

Alfa

AF:

0.00196

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 22, 2011

93062-9C>T in intron 306 of TTN: This variant is not expected to have clinical s ignificance because it is located outside the conserved +/- 1, 2 region of the s plicing consensus sequence and as part of a poly T stretch. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.054

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over