4-87610957-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate
The NM_014208.3(DSPP):c.49C>T(p.Pro17Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P17L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014208.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135284
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461168Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726934
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 17 of the DSPP protein (p.Pro17Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with dentinogenesis imperfecta (PMID: 17686168, 18521831; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1458861). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at