rs1555799865
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_198994.3(TGM6):βc.841delβ(p.Leu281CysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
TGM6
NM_198994.3 frameshift
NM_198994.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.329
Genes affected
TGM6 (HGNC:16255): (transglutaminase 6) The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM6 | NM_198994.3 | c.841del | p.Leu281CysfsTer10 | frameshift_variant | 6/13 | ENST00000202625.7 | |
TGM6 | NM_001254734.2 | c.841del | p.Leu281CysfsTer10 | frameshift_variant | 6/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM6 | ENST00000202625.7 | c.841del | p.Leu281CysfsTer10 | frameshift_variant | 6/13 | 1 | NM_198994.3 | P1 | |
TGM6 | ENST00000381423.1 | c.841del | p.Leu281CysfsTer10 | frameshift_variant | 6/12 | 1 | |||
TGM6 | ENST00000477505.1 | n.472del | non_coding_transcript_exon_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151988Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461610Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727084
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151988Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74230
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2023 | This sequence change creates a premature translational stop signal (p.Leu281Cysfs*10) in the TGM6 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TGM6 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGM6-related conditions. ClinVar contains an entry for this variant (Variation ID: 448681). 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. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at