rs72648903

Positions:

• chr2-178749235-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.13165G>A​(p.Val4389Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,611,590 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.04

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020809174).
• BP6: Variant 2-178749235-C-T is Benign according to our data. Variant chr2-178749235-C-T is described in ClinVar as [Benign]. Clinvar id is 47749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178749235-C-T is described in Lovd as [Benign]. Variant chr2-178749235-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5	c.13165G>A	p.Val4389Ile	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+3889G>A		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.13165G>A	p.Val4389Ile	missense_variant	46/46	5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+3889G>A		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1223+6265C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2418 AN: 151980 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00394 AC: 980 AN: 248640 Hom.: 26 AF XY: 0.00297 AC XY: 400 AN XY: 134606

Gnomad AFR exome AF: 0.0545

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00163 AC: 2383 AN: 1459492 Hom.: 62 Cov.: 36 AF XY: 0.00138 AC XY: 999 AN XY: 726052

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.0160 AC: 2437 AN: 152098 Hom.: 73 Cov.: 32 AF XY: 0.0153 AC XY: 1137 AN XY: 74374

Gnomad4 AFR AF: 0.0562

Gnomad4 AMR AF: 0.00374

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00291 Hom.: 22

Bravo AF: 0.0184

ESP6500AA AF: 0.0502 AC: 221

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00522 AC: 633

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2012	Val4389Ile in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 5% (221/4400) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs72648903). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TTN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.7
DANN	Benign	0.60
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.11
Sift	Benign	0.093	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.093
MVP		0.23
ClinPred		0.010	T
GERP RS		3.4

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: rs72648903; hg19: chr2-179613962;