rs752564961
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_004260.4(RECQL4):c.1187C>T(p.Thr396Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,712 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T396A) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1187C>T | p.Thr396Ile | missense_variant | 6/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1187C>T | p.Thr396Ile | missense_variant | 6/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.116C>T | p.Thr39Ile | missense_variant | 5/20 | 1 | |||
RECQL4 | ENST00000532846.2 | c.74C>T | p.Thr25Ile | missense_variant | 2/9 | 5 | |||
RECQL4 | ENST00000524998.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000485 AC: 12AN: 247170Hom.: 0 AF XY: 0.0000743 AC XY: 10AN XY: 134656
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460522Hom.: 0 Cov.: 66 AF XY: 0.0000372 AC XY: 27AN XY: 726512
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74336
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.Thr396Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs752564961) and in Clinvar (classified as a VUS by Invitae for Baller-Gerold syndrome). The variant was identified in control databases in 13 of 278542 chromosomes at a frequency of 0.000047 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 12 of 30494 chromosomes (freq: 0.000394) and European (non-Finnish) in 1 of 127026 chromosomes (freq: 0.000008); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence and one of four in silico or computational prediction software programs (SpliceSiteFinder-Like) predicts the loss of a 3' splice site at c.1189. It should be noted that there is not a known 3' splice site at this location, and that this location is predicted as a splice site in the wildtype only by SpliceSiteFinder and MaxEntScan but not by NNSPLICE and GeneSplicer. The p.Thr396 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 | Aug 17, 2023 | This variant is present in population databases (rs752564961, gnomAD 0.04%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 569828). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 396 of the RECQL4 protein (p.Thr396Ile). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at