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rs386833845

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004260.4(RECQL4):c.1573del(p.Cys525AlafsTer33) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C525C) has been classified as Likely benign. 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 0.576
Variant links:
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 UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.1573del p.Cys525AlafsTer33 frameshift_variant 9/21 ENST00000617875.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.1573del p.Cys525AlafsTer33 frameshift_variant 9/211 NM_004260.4 P1
RECQL4ENST00000621189.4 linkuse as main transcriptc.502del p.Cys168AlafsTer33 frameshift_variant 8/201
RECQL4ENST00000532846.2 linkuse as main transcriptc.428del p.Cys144AlafsTer33 frameshift_variant 5/95
RECQL4ENST00000688394.1 linkuse as main transcriptn.596del non_coding_transcript_exon_variant 3/4

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152168
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000241
AC:
59
AN:
245124
Hom.:
0
AF XY:
0.000239
AC XY:
32
AN XY:
133808
show subpopulations
Gnomad AFR exome
AF:
0.0000667
Gnomad AMR exome
AF:
0.000117
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000132
Gnomad FIN exome
AF:
0.0000474
Gnomad NFE exome
AF:
0.000416
Gnomad OTH exome
AF:
0.000503
GnomAD4 exome
AF:
0.000409
AC:
597
AN:
1459566
Hom.:
0
Cov.:
33
AF XY:
0.000404
AC XY:
293
AN XY:
725978
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000202
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.0000384
Gnomad4 NFE exome
AF:
0.000494
Gnomad4 OTH exome
AF:
0.000332
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152286
Hom.:
0
Cov.:
34
AF XY:
0.000336
AC XY:
25
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000426
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.000506
EpiCase
AF:
0.000436
EpiControl
AF:
0.000653

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, criteria provided, single submitterclinical testingGeneDxDec 16, 2022Frameshift 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, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022RECQL4: PVS1, PS4:Moderate -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Baller-Gerold syndrome Pathogenic:2Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2006- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 25, 2024This 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. -
Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 09, 2021Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 06, 2022- -
B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJan 15, 2016- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2021The 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 providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
High grade surface osteosarcoma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJul 20, 2016- -
Rothmund-Thomson syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 23, 2017- -
Rothmund-Thomson syndrome type 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833845; hg19: chr8-145740366; COSMIC: COSV104618513; COSMIC: COSV104618513; API