rs199473693
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_019032.6(ADAMTSL4):c.767_786delAGGCCTCTGGCACAGAGCCC(p.Gln256fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,744 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q256Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0018 ( 2 hom. )
Consequence
ADAMTSL4
NM_019032.6 frameshift
NM_019032.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.968
Genes affected
ADAMTSL4 (HGNC:19706): (ADAMTS like 4) This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Sep 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is Pathogenic according to our data. Variant chr1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 39555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150553749-CCAGAGCCCAGGCCTCTGGCA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ADAMTSL4 | NM_019032.6 | c.767_786delAGGCCTCTGGCACAGAGCCC | p.Gln256fs | frameshift_variant | 6/19 | ENST00000271643.9 | NP_061905.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ADAMTSL4 | ENST00000271643.9 | c.767_786delAGGCCTCTGGCACAGAGCCC | p.Gln256fs | frameshift_variant | 6/19 | 5 | NM_019032.6 | ENSP00000271643.4 |
Frequencies
GnomAD3 genomes 0.00118 AC: 180AN: 151926Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00121 AC: 303AN: 250950Hom.: 0 AF XY: 0.00116 AC XY: 157AN XY: 135628
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GnomAD4 exome AF: 0.00182 AC: 2656AN: 1461700Hom.: 2 AF XY: 0.00172 AC XY: 1250AN XY: 727154
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GnomAD4 genome 0.00118 AC: 180AN: 152044Hom.: 0 Cov.: 30 AF XY: 0.00104 AC XY: 77AN XY: 74340
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ectopia lentis 2, isolated, autosomal recessive Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 26, 2017 | The ADAMTSL4 c.767_786delAGGCCTCTGGCACAGAGCCC (p.Gln256ProfsTer38) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Gln256ProfsTer38 variant has been reported in at least six studies in which it is found in a total of 39 individuals with ectopia lentis from at least 12 families, including in 33 individuals in a homozygous state (of whom at least 11 are related), five individuals in a compound heterozygous state and in one individual in a heterozygous state (Aragon-Martin et al. 2010; Christensen et al. 2010; Neuhann et al. 2011; Chandra et al. 2012; Chandra et al. 2013; Neuhann et al. 2015). The variant has also been found in a heterozygous state in eight unaffected family members. The p.Gln256ProfsTer38 variant was observed in a heterozygous state in five of 550 control individuals (Christensen et al. 2010; Neuhann et al. 2011) and is reported at a frequency of 0.002423 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of frameshift variants, the p.Gln256ProfsTer38 variant is classified as pathogenic for ectopia lentis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 24, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 24, 2022 | The ADAMTSL4 c.767_786del variant is classified as a PATHOGENIC VARIANT (PVS1, PS4, PP5) This variant is a 20-base pair deletion in exon 6 of the ADAMTSL4 gene which results in a frameshift starting with codon Glutamine 256, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Q256PfsX38. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay (PVS1). This variant is common pathogenic variant in the ADAMTSL4 gene, and has been previously reported in many individuals with Ectopia lentis in both the homozygous or compound heterozygous state (PMID: 21051722, 22871183, 28642162, 20564469) (PS4). The variant is in dbSNP (rs199473693) and has been reported in population databases (gnomAD: 344/282186, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 39555) and HGMD (Accession No: CD104803) as Pathogenic (PP5). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 19, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ectopia lentis et pupillae (MIM#225200), isolated ectopia lentis (MIM#225100) and craniosynostosis with ectopia lentis (MONDO:0011347; PMID: 35378950). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotype may vary significantly among patients, even within the same family (PMID: 22338190). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (344 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in eight unrelated homozygous individuals and two compound heterozygous individuals with isolated ectopia lentis (PMID: 20564469, 21051722). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_019032.5(ADAMTSL4):c.1656del; p.(Thr553Profs*32)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 09, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Feb 01, 2022 | PM3, PVS1, PP3, PP5, PS4, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 15, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20564469, 22871183, 21051722, 27848971, 23426735, 20702823, 22736615, 28642162, 28394649, 31980526, 31282960, 34426522, 31589614, 33726816) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 11, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | ADAMTSL4: PM3:Very Strong, PVS1, PP1:Strong, PM2:Supporting, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Gln256Profs*38) in the ADAMTSL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADAMTSL4 are known to be pathogenic (PMID: 20564469, 28642162). This variant is present in population databases (rs587691401, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with ectopia lentis (PMID: 2056446, 21051722, 22736615, 22871183, 25975359). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39555). For these reasons, this variant has been classified as Pathogenic. - |
Ectopia lentis et pupillae Pathogenic:2Other:2
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 06-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 24, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Ectopia lentis et pupillae;C3541474:Ectopia lentis 2, isolated, autosomal recessive Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jul 21, 2022 | This variant has been reported in the literature in the homozygous and compound heterozygous states in numerous individuals with ectopia lentis, segregating with disease in at least 6 affected family members (Selected publications: Aragon-Martin 2010 PMID: 20564469; Christensen 2010 PMID: 20702823; Neuhann 2011 PMID: 21051722; Chandra 2012 PMID: 22736615). This variant is present in 0.2% (307/128702) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-150526225-CCAGAGCCCAGGCCTCTGGCA-C?dataset=gnomad_r2_1). Of note, this variant has been described as or suggested to be a founder mutation in multiple European populations (Christensen 2010 PMID: 20702823; Neuhann 2011 PMID: 21051722; Overwater 2017 PMID: 28642162). This variant is present in ClinVar, with several laboratories classifying it as pathogenic (Variation ID: 39555). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 38 amino acids downstream from this location which results in an absent or abnormal protein; loss of function variants are a known mechanism of disease for this gene (Rødahl 2020 PMID: 22338190). In summary, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2024 | - - |
Ectopia lentis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 14, 2014 | The p.Gln256ProfsX38 variant in ADAMTSL4 has been reported in >20 compound heter ozygous or homozygous individuals with ectopia lentis and was found to segregate with disease in 6 affected relatives from 5 families (Aragon -Martin 2010, Chri stensen 2010, Neuhann 2011, Chandra 2013, Overwater 2017). The p.Gln256ProfsX38 variant has been identified in 0.24% (306/126278) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP r s199473693). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 256 and leads to a premature termination codo n 38 amino acids downstream. This alteration has been shown to lead to a truncat ed mRNA (Christensen 2010) and is predicted to lead to a truncated or absent pro tein. Complete loss-of-function of the ADAMTSL4 gene is an established disease m echanism in individuals with ectopia lentis. In summary, this variant meets our criteria to be classified as pathogenic for ectopia lentis in an autosomal reces sive manner based upon segregation studies and the impact of the variant. ACMG/A MP Criteria applied: PVS1; PM3_Very strong; PP1_Moderate. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2024 | The c.767_786del20 (p.Q256Pfs*38) alteration, located in exon 6 (coding exon 4) of the ADAMTSL4 gene, consists of a deletion of 20 nucleotides from position 767 to 786, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.767_786del20 allele has an overall frequency of 0.122% (344/282186) total alleles studied. The highest observed frequency was 0.239% (307/128702) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other ADAMTSL4 variant(s) in individual(s) with features consistent with ADAMTSL4-related ectopia lentis (Overwater, 2017; Lenassi, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
Craniosynostosis with ectopia lentis Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Cunningham Lab, Seattle Childrens Research Institute | Nov 01, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at