rs72648909

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_133379.5(TTN):c.14806A>T(p.Thr4936Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,613,260 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: 2.11

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028660893).

BP6

Variant 2-178747594-T-A is Benign according to our data. Variant chr2-178747594-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47777.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4, not_provided=1}. Variant chr2-178747594-T-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.14806A>T	p.Thr4936Ser	missense_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+5530A>T		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.14806A>T	p.Thr4936Ser	missense_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+5530A>T		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000780

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000523

AC:

131

AN:

250424

Hom.:

AF XY:

0.000584

AC XY:

AN XY:

135320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000928

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000850

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000741

AC:

1083

AN:

1461222

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

536

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000904

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000434

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000781

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000699

Hom.:

Bravo

AF:

0.000502

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000819

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3Other:1

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 28, 2014

GeneDx

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Jan 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.10360+5530A>T is located at a position not widely known to affect splicing. This variant corresponds to c.14806A>T p.Thr4936Ser in NM_133379. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00052 in 250424 control chromosomes. The observed variant frequency is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing autosomal dominant dilated cardiomyopathy (0.00039). c.10360+5530A>T has been reported in the multiply compound heterozygous state in the literature in at least 1 individual affected with dilated cardiomyopathy, without strong evidence for causality (Pugh_2014). These report(s) do not provide unequivocal conclusions about association of the variant with TTN-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 47777). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 28, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr4936Ser variant in TTN is classified as likely benign because it has been identified in 0.09% (32/35326) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also located in an exon that is not highly expressed in the heart and is only present in a transcript (Novex -3) whose function is unclear. ACMG/AMP Criteria applied: BP1, BS1. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Aug 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.97

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.33

M_CAP

Benign

0.068

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.79

PROVEAN

Benign

0.16

REVEL

Benign

0.056

Sift

Benign

0.35

Sift4G

Benign

0.48

Polyphen

0.45

Vest4

0.20

MutPred

0.26

Loss of sheet (P = 0.0104);

MVP

0.75

ClinPred

0.043

GERP RS

4.6

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

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