rs137853232
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_004260.4(RECQL4):c.3061C>T(p.Arg1021Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,612,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1021Q) has been classified as Likely benign.
Frequency
Consequence
NM_004260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.3061C>T | p.Arg1021Trp | missense_variant | 18/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.3061C>T | p.Arg1021Trp | missense_variant | 18/21 | 1 | NM_004260.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152258Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000365 AC: 9AN: 246686Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134642
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1459818Hom.: 0 Cov.: 79 AF XY: 0.0000248 AC XY: 18AN XY: 726148
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152376Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74514
ClinVar
Submissions by phenotype
Baller-Gerold syndrome Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1021 of the RECQL4 protein (p.Arg1021Trp). This variant is present in population databases (rs137853232, gnomAD 0.007%). This missense change has been observed in individual(s) with Baller-Gerold syndrome and Rothmund-Thomson syndrome (PMID: 15897384, 15964893, 23899764, 24635570). 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: 6073). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
RECQL4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | The RECQL4 c.3061C>T variant is predicted to result in the amino acid substitution p.Arg1021Trp. This variant has been reported as causative for Rothmund-Thomson / RAPADILINO syndrome (Kellermayer et al. 2005. PubMed ID: 15897384; Van Maldergem et al. 2005. PubMed ID: 15964893). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at