rs184740744
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001267550.2(TTN):c.14765G>A(p.Ser4922Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,802 control chromosomes in the GnomAD database, including 59 homozygotes. 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 Likely benign (★★).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.14765G>A | p.Ser4922Asn | missense_variant | Exon 50 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.14765G>A | p.Ser4922Asn | missense_variant | Exon 50 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.00190 AC: 289AN: 152166Hom.: 6 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00587 AC: 1460AN: 248644 AF XY: 0.00414 show subpopulations
GnomAD4 exome AF: 0.00121 AC: 1764AN: 1461518Hom.: 53 Cov.: 29 AF XY: 0.000970 AC XY: 705AN XY: 727032 show subpopulations
Age Distribution
GnomAD4 genome 0.00192 AC: 292AN: 152284Hom.: 6 Cov.: 33 AF XY: 0.00207 AC XY: 154AN XY: 74464 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:6
p.Ser3678Asn in exon 47 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 4.3% (495/11530) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs184740744). In addition, multiple mammals carry an asparagine (Asn) at t his position, despite high amino acid conservation nearby, supporting that this change would be tolerated.
Variant summary: TTN c.11033G>A (p.Ser3678Asn) results in a conservative amino acid change in the encoded protein sequence. Two of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0059 in 248644 control chromosomes in the gnomAD database, including 41 homozygotes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
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.
not provided Benign:3
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Cardiomyopathy Benign:2
Early-onset myopathy with fatal cardiomyopathy Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Tibial muscular dystrophy Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Myopathy, myofibrillar, 9, with early respiratory failure Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Dilated cardiomyopathy 1G Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at