rs397517724

chr2-178562521-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001267550.2(TTN):c.83611A>T(p.Thr27871Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T27871I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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-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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.15088665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.83611A>T	p.Thr27871Ser	missense_variant	326/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2044-20051T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.83611A>T	p.Thr27871Ser	missense_variant	326/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-35075T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2013

The Thr25303Ser variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though it may be p resent in other populations. Threonine at position 25303 is conserved in mammals but not in evolutionarily distant species, and a serine (Ser; this variant) is present in frog and tetraodon. Computational analyses (biochemical amino acid pr operties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or a gainst an impact to the protein. Additional information is needed to fully asses s the clinical significance of the Thr25303Ser variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Benign	0.86
Eigen	Benign	-0.093
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;N;.;.;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.13	T;T;.;.;T;T;.
Polyphen		0.0090	.;.;.;B;.;.;B
Vest4		0.20
MutPred		0.48		.;.;.;Gain of glycosylation at T26230 (P = 0.0606);.;.;Gain of glycosylation at T26230 (P = 0.0606);
MVP		0.18
MPC		0.077
ClinPred		0.15	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs397517724; hg19: chr2-179427248;