rs151253841

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133379.5(TTN):โ€‹c.16001C>Tโ€‹(p.Pro5334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,609,320 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (โ˜…โ˜…).

Frequency

Genomes: ๐‘“ 0.0010 ( 5 hom., cov: 32)
Exomes ๐‘“: 0.0017 ( 57 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

4
3
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0089713335).
BP6
Variant 2-178746399-G-A is Benign according to our data. Variant chr2-178746399-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178746399-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00105 (159/152014) while in subpopulation SAS AF= 0.0284 (137/4820). AF 95% confidence interval is 0.0245. There are 5 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_133379.5 linkuse as main transcriptc.16001C>T p.Pro5334Leu missense_variant 46/46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7
TTNNM_001267550.2 linkuse as main transcriptc.11312-4478C>T intron_variant ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000360870.10 linkuse as main transcriptc.16001C>T p.Pro5334Leu missense_variant 46/465 NM_133379.5 ENSP00000354117.4 Q8WZ42-6
TTNENST00000589042.5 linkuse as main transcriptc.11312-4478C>T intron_variant 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000994
AC:
151
AN:
151896
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000263
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0286
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000884
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00341
AC:
842
AN:
246704
Hom.:
15
AF XY:
0.00462
AC XY:
616
AN XY:
133372
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000295
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.0277
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000627
Gnomad OTH exome
AF:
0.00118
GnomAD4 exome
AF:
0.00171
AC:
2491
AN:
1457306
Hom.:
57
Cov.:
33
AF XY:
0.00245
AC XY:
1778
AN XY:
724612
show subpopulations
Gnomad4 AFR exome
AF:
0.0000904
Gnomad4 AMR exome
AF:
0.0000679
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000758
Gnomad4 SAS exome
AF:
0.0269
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000568
Gnomad4 OTH exome
AF:
0.00196
GnomAD4 genome
AF:
0.00105
AC:
159
AN:
152014
Hom.:
5
Cov.:
32
AF XY:
0.00143
AC XY:
106
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0284
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000884
Gnomad4 OTH
AF:
0.00427
Alfa
AF:
0.000149
Hom.:
0
Bravo
AF:
0.000291
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00404
AC:
491
Asia WGS
AF:
0.0200
AC:
68
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 20, 2014p.Pro5334Leu in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 3.0% (482/16240) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs151253841). -
Benign, criteria provided, single submitterclinical testingAl Jalila Childrenโ€™s Genomics Center, Al Jalila Childrens Speciality HospitalMar 19, 2020- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJul 03, 2019- -
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Limb-girdle muscular dystrophy, recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Early-onset myopathy with fatal cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Tibial muscular dystrophy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
MetaRNN
Benign
0.0090
T
MetaSVM
Benign
-0.44
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PROVEAN
Benign
-0.72
N
REVEL
Uncertain
0.36
Sift
Benign
0.065
T
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.66
MVP
0.76
ClinPred
0.12
T
GERP RS
5.9

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs151253841; hg19: chr2-179611126; COSMIC: COSV100592792; COSMIC: COSV100592792; API