Genetic Variant TTN:p.Gly3751Val (chr2-178756224-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001267550.2(TTN):c.11252G>T(p.Gly3751Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000693 in 1,443,450 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3751D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

Splicing: ADA: 0.01581

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.78

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.11252G>T	p.Gly3751Val	missense_variant, splice_region_variant	Exon 46 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.10303+2760G>T		intron_variant	Intron 44 of 45	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.11252G>T	p.Gly3751Val	missense_variant, splice_region_variant	Exon 46 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.10303+2760G>T		intron_variant	Intron 44 of 45	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443450

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33062

American (AMR)

AF:

0.00

AC:

AN:

44098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25584

East Asian (EAS)

AF:

0.00

AC:

AN:

39376

South Asian (SAS)

AF:

0.00

AC:

AN:

84814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1099120

Other (OTH)

AF:

0.00

AC:

AN:

59570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.47

T;T

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.68

PhyloP100

3.8

PROVEAN

Benign

-0.87

.;N

REVEL

Benign

0.086

Sift

Benign

0.13

.;T

Vest4

0.26

MutPred

0.26

.;Loss of disorder (P = 0.052);

MVP

0.71

MPC

0.27

ClinPred

0.62

GERP RS

4.2

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.016

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over