8-144513445-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_004260.4(RECQL4):c.2236G>A(p.Ala746Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,609,658 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A746A) has been classified as Benign.
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.2236G>A | p.Ala746Thr | missense_variant | 14/21 | ENST00000617875.6 | NP_004251.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.2236G>A | p.Ala746Thr | missense_variant | 14/21 | 1 | NM_004260.4 | ENSP00000482313 | P1 | |
RECQL4 | ENST00000621189.4 | c.1165G>A | p.Ala389Thr | missense_variant | 13/20 | 1 | ENSP00000483145 | |||
ENST00000580385.1 | n.272-161C>T | intron_variant, non_coding_transcript_variant | 3 | |||||||
RECQL4 | ENST00000534626.6 | c.607G>A | p.Ala203Thr | missense_variant | 5/8 | 5 | ENSP00000477457 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000536 AC: 13AN: 242540Hom.: 0 AF XY: 0.0000677 AC XY: 9AN XY: 132998
GnomAD4 exome AF: 0.0000398 AC: 58AN: 1457408Hom.: 0 Cov.: 46 AF XY: 0.0000496 AC XY: 36AN XY: 725182
GnomAD4 genome AF: 0.000138 AC: 21AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74390
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Baller-Gerold syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 12, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 746 of the RECQL4 protein (p.Ala746Thr). This variant is present in population databases (rs758736784, gnomAD 0.02%). 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: 407043). 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%. 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