rs386833845
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004260.4(RECQL4):c.1573delT(p.Cys525fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,611,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
RECQL4
NM_004260.4 frameshift
NM_004260.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.576
Genes affected
RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]
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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 8-144514982-CA-C is Pathogenic according to our data. Variant chr8-144514982-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 6066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514982-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr8-144514982-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1573delT | p.Cys525fs | frameshift_variant | 9/21 | ENST00000617875.6 | NP_004251.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1573delT | p.Cys525fs | frameshift_variant | 9/21 | 1 | NM_004260.4 | ENSP00000482313.2 | ||
RECQL4 | ENST00000621189.4 | c.502delT | p.Cys168fs | frameshift_variant | 8/20 | 1 | ENSP00000483145.1 | |||
RECQL4 | ENST00000532846.2 | c.427delT | p.Cys143fs | frameshift_variant | 5/9 | 5 | ENSP00000476551.1 | |||
RECQL4 | ENST00000688394.1 | n.596delT | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes AF: 0.000329 AC: 50AN: 152168Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000241 AC: 59AN: 245124Hom.: 0 AF XY: 0.000239 AC XY: 32AN XY: 133808
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GnomAD4 exome AF: 0.000409 AC: 597AN: 1459566Hom.: 0 Cov.: 33 AF XY: 0.000404 AC XY: 293AN XY: 725978
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GnomAD4 genome AF: 0.000328 AC: 50AN: 152286Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 25AN XY: 74466
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | RECQL4: PVS1, PS4:Moderate - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 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: 31829210, 29367366, 28423363, 12734318, 12838562, 18716613, 15964893, 30947698, 31604778, 29625052, 32081490, 31980526, 31589614, 10678659, 34308104) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Baller-Gerold syndrome Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Cys525Alafs*33) in the RECQL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs386833845, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund–Thomson syndrome (PMID: 10678659, 12838562, 15897384, 15964893, 18716613, 20113479, 29367366, 31829210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.2886delT. ClinVar contains an entry for this variant (Variation ID: 6066). For these reasons, this variant has been classified as Pathogenic. - |
B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 15, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 2021 | The c.1573delT (p.C525Afs*33) alteration, located in exon 9 (coding exon 9) of the RECQL4 gene, consists of a deletion of one nucleotide at position 1573, causing a translational frameshift with a predicted alternate stop codon after 33 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous and compound heterozygous states in individuals with RECQL4-related disorders with and without malignancies (Van Maldergem, 2006; Siitonen, 2009). Based on the available evidence, this alteration is classified as pathogenic. - |
Rapadilino syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
High grade surface osteosarcoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 20, 2016 | - - |
Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2022 | - - |
Rothmund-Thomson syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 23, 2017 | - - |
Rothmund-Thomson syndrome type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2006 | - - |
RECQL4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 09, 2021 | Variant summary: RECQL4 c.1573delT (p.Cys525AlafsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by other laboratories (ClinVar). The variant allele was found at a frequency of 0.00024 in 245124 control chromosomes (gnomAD). c.1573delT has been reported in the literature in multiple individuals affected with RECQL4-Related Disorders (e.g. Siitonen_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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