13-94578001-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014305.4(TGDS):c.825+4T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,720 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
TGDS
NM_014305.4 splice_donor_region, intron
NM_014305.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00009617
2
Clinical Significance
Conservation
PhyloP100: 0.199
Genes affected
TGDS (HGNC:20324): (TDP-glucose 4,6-dehydratase) The protein encoded by this gene is a member of the short-chain dehydrogenases/reductases (SDR) superfamily, and is thought to contain a nicotinamide adenine dinucleotide (NAD) binding domain. This large SDR family of enzymes is involved in the metabolism of a variety of compounds, including prostaglandins, retinoids, lipids, steroid hormones, and xenobiotics. Mutations in this gene have been associated with Catel-Manzke syndrome, which is characterized by Pierre Robin sequence, and radial deviation of the index finger due to the presence of an accessory bone between the index finger and its proximal phalanx. Pierre Robin sequence is defined by an undersized jaw, backwards displacement of the tongue base that causes an obstruction of the airways, and can also be associated with a cleft palate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGDS | NM_014305.4 | c.825+4T>A | splice_donor_region_variant, intron_variant | ENST00000261296.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGDS | ENST00000261296.7 | c.825+4T>A | splice_donor_region_variant, intron_variant | 1 | NM_014305.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250564Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135474
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1460488Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23AN XY: 726458
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74380
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change falls in intron 9 of the TGDS gene. It does not directly change the encoded amino acid sequence of the TGDS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs757254333, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TGDS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1523917). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at