rs886039773
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138927.4(SON):c.5753_5756del(p.Val1918GlufsTer87) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SON
NM_138927.4 frameshift
NM_138927.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.37
Genes affected
SON (HGNC:11183): (SON DNA and RNA binding protein) This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 21-33554981-CAGTT-C is Pathogenic according to our data. Variant chr21-33554981-CAGTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33554981-CAGTT-C is described in Lovd as [Pathogenic]. Variant chr21-33554981-CAGTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SON | NM_138927.4 | c.5753_5756del | p.Val1918GlufsTer87 | frameshift_variant | 3/12 | ENST00000356577.10 | NP_620305.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SON | ENST00000356577.10 | c.5753_5756del | p.Val1918GlufsTer87 | frameshift_variant | 3/12 | 1 | NM_138927.4 | ENSP00000348984 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:24Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
ZTTK syndrome Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 12, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Val1918GlufsTer87 variant in SON was identified by our study in one individual with agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Val1918GlufsTer87 variant in SON has been previously reported in 12 unrelated individuals with ZTTK syndrome (PMID: 34521999, PMID: 27256762, PMID: 27545680, PMID: 27545676) and was found to be de novo in these individuals with confirmed paternity and maternity. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 252929) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1918 and leads to a premature termination codon 87 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SON gene is an established disease mechanism in autosomal dominant ZTTK syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ZTTK syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015). - |
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Sep 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 03, 2023 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Sep 15, 2022 | The variant in c.5753_5756del (p.Val1918Glufs*87) in SON gene is reported as pathogenic/likely pathogenic for ZTTK syndrome in ClinVar (Variation ID: 252929) and pathogenic in the LOVD database v.3.0. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 87 amino acids downstream. It is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has not been identified in the parents, therefore, it can be concluded that the variant is de novo. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 14, 2022 | PVS1, PS2, PS4, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 29, 2022 | _x000D_ Criteria applied: PVS1, PS2_VSTR, PS4, PM2_SUP, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | May 31, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 01, 2021 | The de novo heterozygous four base-pair deletion c.5753_5756del (p.Val1918GlufsTer87) identified in exon 3 (of 12) of the SON gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in patients affected with ZTTK syndrome [PMID: 27545676; PMID: 27545680]. The variant has been reported as pathogenic in ClinVar database by multiple independent laboratories [Variation ID:252929]. The variant is absent from the gnomAD database suggesting it is not a common benign variant in the populations represented in the that database. Based on the available evidence, the de novo heterozygous c.5753_5756del (p.Val1918GlufsTer87) variant identified the SON gene is reported as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 03-16-2017 by The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | Jun 19, 2020 | - - |
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | Jan 14, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 16, 2023 | This sequence change creates a premature translational stop signal (p.Val1918Glufs*87) in the SON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SON are known to be pathogenic (PMID: 27545676, 27545680). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Zhu-Tokita-Takenouchi-Kim syndrome (PMID: 27545676, 27545680). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 252929). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | SON: PM6:Very Strong, PVS1, PM2, PS4:Moderate - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Neurodevelopmental abnormality Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Jun 04, 2020 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2021 | The c.5753_5756delTTAG (p.V1918Efs*87) alteration, located in exon 3 (coding exon 3) of the SON gene, consists of a deletion of 4 nucleotides from position 5753 to 5756, causing a translational frameshift with a predicted alternate stop codon after 87 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as a de novo occurrence in multiple affected individuals (Zhu, 2015; Kim, 2016; Takenouchi, 2016; Tokita, 2016; Ambry internal data). Real-time qPCR showed significantly decreased levels of SON mRNA transcripts in peripheral blood from two individuals harboring this variant, as compared to unaffected individuals negative for the variant (Kim, 2016). Based on the available evidence, this alteration is classified as pathogenic. - |
Hereditary spastic paraplegia 17 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 25, 2021 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Aug 13, 2019 | ACMG classification criteria: PVS1, PS4, PM2, PM6 - |
Global developmental delay;C2315100:Failure to thrive Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 21, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at