20-2394486-G-A
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_198994.3(TGM6):c.42G>A(p.Ser14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,611,560 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0069 ( 13 hom., cov: 32)
Exomes 𝑓: 0.0064 ( 56 hom. )
Consequence
TGM6
NM_198994.3 synonymous
NM_198994.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.47
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 20-2394486-G-A is Benign according to our data. Variant chr20-2394486-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 337902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-2394486-G-A is described in Lovd as [Likely_benign]. Variant chr20-2394486-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.47 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00695 (1058/152276) while in subpopulation NFE AF= 0.00615 (418/68020). AF 95% confidence interval is 0.00566. There are 13 homozygotes in gnomad4. There are 626 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1058 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM6 | NM_198994.3 | c.42G>A | p.Ser14= | synonymous_variant | 2/13 | ENST00000202625.7 | |
TGM6 | NM_001254734.2 | c.42G>A | p.Ser14= | synonymous_variant | 2/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM6 | ENST00000202625.7 | c.42G>A | p.Ser14= | synonymous_variant | 2/13 | 1 | NM_198994.3 | P1 | |
TGM6 | ENST00000381423.1 | c.42G>A | p.Ser14= | synonymous_variant | 2/12 | 1 | |||
TGM6 | ENST00000477505.1 | n.35G>A | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00696 AC: 1059AN: 152158Hom.: 13 Cov.: 32
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GnomAD3 exomes AF: 0.00664 AC: 1654AN: 249090Hom.: 18 AF XY: 0.00657 AC XY: 886AN XY: 134878
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GnomAD4 exome AF: 0.00635 AC: 9267AN: 1459284Hom.: 56 Cov.: 30 AF XY: 0.00621 AC XY: 4511AN XY: 725972
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GnomAD4 genome AF: 0.00695 AC: 1058AN: 152276Hom.: 13 Cov.: 32 AF XY: 0.00841 AC XY: 626AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | TGM6: BP4, BP7, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 20, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Spinocerebellar ataxia type 35 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at