rs760153126
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting
The NM_000371.4(TTR):āc.405C>Gā(p.Ser135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,118 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.000075 ( 0 hom. )
Consequence
TTR
NM_000371.4 synonymous
NM_000371.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -4.42
Genes affected
TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
?
Variant 18-31598636-C-G is Benign according to our data. Variant chr18-31598636-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 412959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-4.42 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 109 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.405C>G | p.Ser135= | synonymous_variant | 4/4 | ENST00000237014.8 | |
LOC124904277 | XR_007066326.1 | n.129-2941G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.405C>G | p.Ser135= | synonymous_variant | 4/4 | 1 | NM_000371.4 | P1 | |
TTR | ENST00000649620.1 | c.405C>G | p.Ser135= | synonymous_variant | 6/6 | P1 | |||
TTR | ENST00000610404.5 | c.309C>G | p.Ser103= | synonymous_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251460Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
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GnomAD4 exome AF: 0.0000746 AC: 109AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727240
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 22, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. - |
Familial amyloid neuropathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at