chr18-31591910-C-CTCA
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000371.4(TTR):c.11_13dup(p.His4dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Likely benign.
Frequency
Consequence
NM_000371.4 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.11_13dup | p.His4dup | inframe_insertion | 1/4 | ENST00000237014.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.11_13dup | p.His4dup | inframe_insertion | 1/4 | 1 | NM_000371.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251416Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135878
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461876Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 727234
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial amyloid neuropathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 326545). This variant has not been reported in the literature in individuals affected with TTR-related conditions. This variant is present in population databases (rs747545126, gnomAD 0.0009%). This variant, c.11_13dup, results in the insertion of 1 amino acid(s) of the TTR protein (p.His4dup), but otherwise preserves the integrity of the reading frame. - |
Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 30, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2017 | A variant of uncertain significance has been identified in the TTR gene. The c.11_13dupATC variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.11_13dupATC variant results in the in-frame duplication of a histidine (H) residue in the signal peptide region of the TTR protein, denoted p.H4dup. Other in-frame deletions and duplications have been reported in the TTR gene, however, none have been reported in this region (Stenson et al., 2014). Furthermore, the residues adjacent to this duplicated residue are not conserved across species. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2018 | The c.11_13dupATC variant (also known as p.H4dup), located in coding exon 1 of the TTR gene. This variant results from an in-frame duplication of 3 nucleotides at positions 11 to 13. This results in the duplication of a histidine residue at codon 4. This amino acid position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at