rs149878929

Positions:

chr2-178751989-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_133379.5(TTN):c.10411G>A(p.Ala3471Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000226 in 1,587,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 6.97

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009629548).

BP6

Variant 2-178751989-C-T is Benign according to our data. Variant chr2-178751989-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (174/150690) while in subpopulation AFR AF= 0.00405 (166/41010). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.10411G>A	p.Ala3471Thr	missense_variant	46/46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+1135G>A		intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.10411G>A	p.Ala3471Thr	missense_variant	46/46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+1135G>A		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

173

AN:

150576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000332

AC:

AN:

226146

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

122496

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.0000708

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:

0.00000946

Gnomad OTH exome

AF:

0.000188

GnomAD4 exome

AF:

0.000129

AC:

185

AN:

1436832

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

714258

show subpopulations

Gnomad4 AFR exome

AF:

0.00498

Gnomad4 AMR exome

AF:

0.000106

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000905

Gnomad4 OTH exome

AF:

0.000186

GnomAD4 genome

AF:

0.00115

AC:

174

AN:

150690

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

73488

show subpopulations

Gnomad4 AFR

AF:

0.00405

Gnomad4 AMR

AF:

0.000464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.00136

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 22, 2015	p.Ala3471Thr in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (50/9948) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs149878929). -

TTN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Other:1

not provided, no classification provided

clinical testing

GeneDx

Jul 25, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.53

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.88

PROVEAN

Benign

-0.020

REVEL

Benign

0.19

Sift

Benign

0.35

Sift4G

Benign

0.63

Polyphen

1.0

Vest4

0.55

MVP

0.55

ClinPred

0.046

GERP RS

5.9

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