8-144514988-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6
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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523N) has been classified as Uncertain significance.
Frequency
Consequence
NM_004260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1568G>C | p.Ser523Thr | missense_variant | 9/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1568G>C | p.Ser523Thr | missense_variant | 9/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.497G>C | p.Ser166Thr | missense_variant | 8/20 | 1 | |||
RECQL4 | ENST00000532846.2 | c.425G>C | p.Ser142Thr | missense_variant | 5/9 | 5 | |||
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
GnomAD3 exomes AF: 0.000246 AC: 60AN: 244018Hom.: 0 AF XY: 0.000240 AC XY: 32AN XY: 133330
GnomAD4 exome AF: 0.000410 AC: 599AN: 1459330Hom.: 0 Cov.: 33 AF XY: 0.000405 AC XY: 294AN XY: 725822
GnomAD4 genome AF: 0.000328 AC: 50AN: 152304Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 25AN XY: 74484
ClinVar
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 | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at