rs386833844
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001413043.1(RECQL4):c.-71C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000277 in 1,589,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
RECQL4
NM_001413043.1 5_prime_UTR_premature_start_codon_gain
NM_001413043.1 5_prime_UTR_premature_start_codon_gain
Scores
3
4
4
Clinical Significance
Conservation
PhyloP100: 7.04
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828
PP5
Variant 8-144515236-G-A is Pathogenic according to our data. Variant chr8-144515236-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144515236-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1397C>T | p.Pro466Leu | missense_variant | 8/21 | ENST00000617875.6 | NP_004251.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1397C>T | p.Pro466Leu | missense_variant | 8/21 | 1 | NM_004260.4 | ENSP00000482313.2 | ||
RECQL4 | ENST00000621189.4 | c.326C>T | p.Pro109Leu | missense_variant | 7/20 | 1 | ENSP00000483145.1 | |||
RECQL4 | ENST00000532846.2 | c.281C>T | p.Pro94Leu | missense_variant | 4/9 | 5 | ENSP00000476551.1 | |||
RECQL4 | ENST00000688394.1 | n.420C>T | non_coding_transcript_exon_variant | 2/4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000237 AC: 5AN: 210890Hom.: 0 AF XY: 0.0000262 AC XY: 3AN XY: 114480
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GnomAD4 exome AF: 0.0000285 AC: 41AN: 1437156Hom.: 0 Cov.: 33 AF XY: 0.0000309 AC XY: 22AN XY: 712906
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 21, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2018 | The P466L variant in the RECQL4 gene has been reported previously in one individual with Rothmund-Thomson syndrome, and in one individual with RAPADALINO syndrome; both of these individuals harbored a frameshift RECQL4 variant in trans with P466L (Jin et al., 2008; Siitonen et al., 2009). Functional studies demonstrate that the P466L variant results in decreased protein activity as compared to wild type (Jensen et al., 2012). The P466L variant is observed in 4/106770 (0.004%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The P466L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P466L as a likely pathogenic variant. - |
Baller-Gerold syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 466 of the RECQL4 protein (p.Pro466Leu). This variant is present in population databases (rs386833844, gnomAD 0.004%). This missense change has been observed in individual(s) with Rothmand-Thompson syndrome (RTS) (PMID: 18504617, 18716613). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RECQL4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RECQL4 function (PMID: 23238538, 33046774). For these reasons, this variant has been classified as Pathogenic. - |
Rapadilino syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D
Polyphen
0.99
.;D
Vest4
MVP
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at