rs377037421

Positions:

• chr2-178617135-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001267550.2(TTN):​c.47860G>A​(p.Ala15954Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000553 in 1,609,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A15954A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 7.85

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.28250653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.47860G>A	p.Ala15954Thr	missense_variant	255/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.47860G>A	p.Ala15954Thr	missense_variant	255/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+19454C>T		intron_variant, non_coding_transcript_variant
	ENST00000605334.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151850 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000700 AC: 17 AN: 242700 Hom.: 0 AF XY: 0.0000683 AC XY: 9 AN XY: 131682

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000535 AC: 78 AN: 1457366 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 39 AN XY: 724696

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.0000478

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151850 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74138

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000581 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 09, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2013	The Ala13386Thr variant in TTN has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/8190 European American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity conclusivel y. Additional information is needed to fully assess the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: TTN c.40156G>A (p.Ala13386Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 1602240 control chromosomes (i.e. in 89 carriers) in the gnomAD database, v4.0 dataset. To our knowledge, no occurrence of c.40156G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

The p.A6889T variant (also known as c.20665G>A), located in coding exon 82 of the TTN gene, results from a G to A substitution at nucleotide position 20665. The alanine at codon 6889 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Benign	0.95
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.7	D;D;.;.;D;D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.47
MVP		0.20
MPC		0.46
ClinPred		0.090	T
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs377037421; hg19: chr2-179481862; COSMIC: COSV59992644; COSMIC: COSV59992644;