chr15-100132006-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_139057.4(ADAMTS17):c.1721+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000291 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
ADAMTS17
NM_139057.4 splice_donor
NM_139057.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.20
Genes affected
ADAMTS17 (HGNC:17109): (ADAM metallopeptidase with thrombospondin type 1 motif 17) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protein, which may promote breast cancer cell growth and survival. Mutations in this gene are associated with a Weill-Marchesani-like syndrome, which is characterized by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. [provided by RefSeq, May 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 15-100132006-C-T is Pathogenic according to our data. Variant chr15-100132006-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAMTS17 | NM_139057.4 | c.1721+1G>A | splice_donor_variant | ENST00000268070.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAMTS17 | ENST00000268070.9 | c.1721+1G>A | splice_donor_variant | 1 | NM_139057.4 | ||||
ADAMTS17 | ENST00000568565.2 | c.1721+1G>A | splice_donor_variant | 5 | P1 | ||||
ADAMTS17 | ENST00000378898.8 | n.1402+1G>A | splice_donor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
4
AN:
152182
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250252Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135430
GnomAD3 exomes
AF:
AC:
8
AN:
250252
Hom.:
AF XY:
AC XY:
4
AN XY:
135430
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727202
GnomAD4 exome
AF:
AC:
43
AN:
1461794
Hom.:
Cov.:
31
AF XY:
AC XY:
22
AN XY:
727202
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74338
GnomAD4 genome
AF:
AC:
4
AN:
152182
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
74338
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
3
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Weill-Marchesani 4 syndrome, recessive Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Imagine Institute | Jun 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2023 | This sequence change affects a donor splice site in intron 12 of the ADAMTS17 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs749116256, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features consistent with Weill-Marchesani-like syndrome (PMID: 19836009). ClinVar contains an entry for this variant (Variation ID: 3155). Studies have shown that disruption of this splice site results in skipping of exon 12 and introduces a premature termination codon (PMID: 19836009). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at