8-144514976-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_004260.4(RECQL4):c.1580C>G(p.Thr527Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,611,844 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T527A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1580C>G | p.Thr527Arg | missense_variant | 9/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1580C>G | p.Thr527Arg | missense_variant | 9/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.509C>G | p.Thr170Arg | missense_variant | 8/20 | 1 | |||
RECQL4 | ENST00000532846.2 | c.437C>G | p.Thr146Arg | missense_variant | 5/9 | 5 | |||
RECQL4 | ENST00000688394.1 | n.603C>G | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245596Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 133998
GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459674Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7AN XY: 726074
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RECQL4 p.Thr527Arg variant was identified in 1 of 1220 proband chromosomes (frequency: 0.00082) from individuals with structural anomalies (Lord_2019_PMID:30712880). The proband was compound heterozygous for the p.T527R variant and a nonsense variant in RECQL4 (Lord_2019_PMID:30712880). The variant was identified in dbSNP (ID: rs766354337) and ClinVar (classified as uncertain significance by Invitae for Baller-Gerold syndrome) but was not identified in LOVD 3.0 or Cosmic. The variant was identified in control databases in 2 of 264196 chromosomes at a frequency of 0.00000757 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: African in 1 of 22550 chromosomes (freq: 0.000044) and European (non-Finnish) in 1 of 116624 chromosomes (freq: 0.000009), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Thr527 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Baller-Gerold syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 527 of the RECQL4 protein (p.Thr527Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 528916). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at