8-144514287-C-T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_004260.4(RECQL4):c.1780G>A(p.Ala594Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,611,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 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. A594V) has been classified as Uncertain significance.
Frequency
Consequence
NM_004260.4 missense
Scores
Clinical Significance
Conservation
Publications
- Baller-Gerold syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
- Rothmund-Thomson syndromeInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Rothmund-Thomson syndrome type 2Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
- osteosarcomaInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- rapadilino syndromeInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.0000205 AC: 5AN: 244264 AF XY: 0.0000150 show subpopulations
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1459120Hom.: 0 Cov.: 36 AF XY: 0.0000262 AC XY: 19AN XY: 725818 show subpopulations
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74316 show subpopulations
ClinVar
Submissions by phenotype
Baller-Gerold syndrome Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 594 of the RECQL4 protein (p.Ala594Thr). This variant is present in population databases (rs376364416, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 583123). 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. -
RECQL4-related disorder Uncertain:1
The RECQL4 c.1780G>A variant is predicted to result in the amino acid substitution p.Ala594Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Ovarian cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at