rs397517666

chr2-178775947-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001267550.2(TTN):c.5917A>G(p.Thr1973Ala) 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. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.00100

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 Likely_benign. 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=0.04426515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.5917A>G	p.Thr1973Ala	missense_variant	28/363	ENST00000589042.5
TTN	NM_133379.5	c.5917A>G	p.Thr1973Ala	missense_variant	28/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.5917A>G	p.Thr1973Ala	missense_variant	28/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.5917A>G	p.Thr1973Ala	missense_variant	28/46	5	NM_133379.5
TTN-AS1	ENST00000659121.1	n.3374T>C		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Dec 16, 2011

The Thr1973Ala variant has not been reported in the literature but has been iden tified by our laboratory in 1 individual wiht arrhythmia and mold cardia dilatio n. Threonine (Thr) at position 1973 is not well conserved across mammals (two naturally carry the amnino acid present in this patient), suggesting that a chan ge may be tolerated. In addition, two computational tools (AlignGVGD and SIFT) predict this variant to be benign although their accuracy is unknown. This varia nt is less likely pathogenic but additional data is needed to clarify its clinic al significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Benign	0.82
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.64	T;T;T;.;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.044	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;N;.;.;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.78	T;T;.;.;T;T;.;T
Polyphen		0.0, 0.0010	.;.;.;B;.;.;B;B
Vest4		0.20
MutPred		0.16		Loss of phosphorylation at T1973 (P = 0.038);.;Loss of phosphorylation at T1973 (P = 0.038);Loss of phosphorylation at T1973 (P = 0.038);.;.;Loss of phosphorylation at T1973 (P = 0.038);Loss of phosphorylation at T1973 (P = 0.038);
MVP		0.092
MPC		0.082
ClinPred		0.029	T
GERP RS		-0.40

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: rs397517666; hg19: chr2-179640674;