rs1060501383
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004260.4(RECQL4):c.1568_1573delinsCCCCC(p.Ser523ThrfsTer35) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S523S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Consequence
RECQL4
NM_004260.4 frameshift
NM_004260.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.00
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 8-144514983-AGGGGC-GGGGG is Pathogenic according to our data. Variant chr8-144514983-AGGGGC-GGGGG is described in ClinVar as [Pathogenic]. Clinvar id is 407029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1568_1573delinsCCCCC | p.Ser523ThrfsTer35 | frameshift_variant | 9/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1568_1573delinsCCCCC | p.Ser523ThrfsTer35 | frameshift_variant | 9/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.497_502delinsCCCCC | p.Ser166ThrfsTer35 | frameshift_variant | 8/20 | 1 | |||
RECQL4 | ENST00000532846.2 | c.423_428delinsCCCCC | p.Ser142ThrfsTer35 | frameshift_variant | 5/9 | 5 | |||
RECQL4 | ENST00000688394.1 | n.591_596delinsCCCCC | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Also known as c.1573delT; 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29642415, 29367366, 27247962, 15964893, 15897384, 12838562, 12734318, 10678659, 18616953) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | RECQL4: PVS1, PM2, PS4:Moderate, BP1 - |
Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 14, 2021 | Variant summary: RECQL4 c.1568_1573delinsCCCCC (p.Ser523ThrfsX35) 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. The variant allele was found at a frequency of 0.00025 in 276484 control chromosomes (gnomAD). c.1568_1573delinsCCCCC [described in the literature as two variants in cis: c.1568G>C (p.Ser523Thr) and c.1573delT (p.Cys525AlafsX33)] has been reported in multiple individuals affected with RECQL4-Related Disorders (e.g. Siitonen_2009, Suter_2016, Colombo_2018, Salih_2018). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
RECQL4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2023 | The RECQL4 c.1568_1573delinsCCCCC variant is predicted to result in a frameshift and premature protein termination (p.Ser523Thrfs*35). This variant (also denoted as c.1568G>C;c.1573delT) has been reported in the compound heterozygous state in multiple individuals with Rothmund-Thomson syndrome (Suter et al. 2016. PubMed ID: 27247962; Salih et al 2018. PubMed ID: 29367366; Colombo et al. 2018. PubMed ID: 29642415). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in RECQL4 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at