rs786200900
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_203486.3(DLL3):c.945_946del(p.Ala317ArgfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T315T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_203486.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLL3 | NM_203486.3 | c.945_946del | p.Ala317ArgfsTer17 | frameshift_variant | 6/9 | ENST00000356433.10 | |
DLL3 | NM_016941.4 | c.945_946del | p.Ala317ArgfsTer17 | frameshift_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLL3 | ENST00000356433.10 | c.945_946del | p.Ala317ArgfsTer17 | frameshift_variant | 6/9 | 2 | NM_203486.3 | P1 | |
DLL3 | ENST00000205143.4 | c.945_946del | p.Ala317ArgfsTer17 | frameshift_variant | 6/8 | 1 | |||
DLL3 | ENST00000600437.1 | n.1025_1026del | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
DLL3 | ENST00000596614.5 | c.410-1736_410-1735del | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461890Hom.: 0 AF XY: 0.0000220 AC XY: 16AN XY: 727248
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
Spondylocostal dysostosis 1, autosomal recessive Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2000 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Jun 28, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Ala317Argfs*17) in the DLL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLL3 are known to be pathogenic (PMID: 12746394). This variant is present in population databases (rs786200900, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 10742114). ClinVar contains an entry for this variant (Variation ID: 6829). 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