rs754735053
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_004260.4(RECQL4):c.1568G>C(p.Ser523Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,611,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
RECQL4
NM_004260.4 missense
NM_004260.4 missense
Scores
1
10
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 8-144514988-C-G is Benign according to our data. Variant chr8-144514988-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1568G>C | p.Ser523Thr | missense_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.1568G>C | p.Ser523Thr | missense_variant | 9/21 | 1 | NM_004260.4 | ENSP00000482313 | P1 | |
RECQL4 | ENST00000621189.4 | c.497G>C | p.Ser166Thr | missense_variant | 8/20 | 1 | ENSP00000483145 | |||
RECQL4 | ENST00000532846.2 | c.425G>C | p.Ser142Thr | missense_variant | 5/9 | 5 | ENSP00000476551 | |||
RECQL4 | ENST00000688394.1 | n.591G>C | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes AF: 0.000329 AC: 50AN: 152186Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000246 AC: 60AN: 244018Hom.: 0 AF XY: 0.000240 AC XY: 32AN XY: 133330
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GnomAD4 exome AF: 0.000410 AC: 599AN: 1459330Hom.: 0 Cov.: 33 AF XY: 0.000405 AC XY: 294AN XY: 725822
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GnomAD4 genome AF: 0.000328 AC: 50AN: 152304Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 25AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 2021 | The c.1568G>C (p.S523T) alteration is located in exon 9 (coding exon 9) of the RECQL4 gene. This alteration results from a G to C substitution at nucleotide position 1568, causing the serine (S) at amino acid position 523 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Rothmund-Thomson syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 19, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 30, 2021 | - - |
Baller-Gerold syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 523 of the RECQL4 protein (p.Ser523Thr). This variant is present in population databases (rs754735053, gnomAD 0.05%). This missense change has been observed in cis with c.1573del (p.Cys525Alafs*33) in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund–Thomson syndrome (PMID: 12838562, 15964893, 27247962, 29367366, 29642415). This variant has not been reported in isolation in the literature in individuals affected with RECQL4-related conditions. This variant is also known as g.2881G>C. ClinVar contains an entry for this variant (Variation ID: 259258). 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 not expected to disrupt RECQL4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | RECQL4: BP2, BP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Uncertain
T;T
PrimateAI
Benign
T
Sift4G
Benign
T;D
Polyphen
0.64
.;P
Vest4
MVP
GERP RS
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