8-144516030-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004260.4(RECQL4):c.1089C>A(p.Tyr363Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,438 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y363Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004260.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1089C>A | p.Tyr363Ter | stop_gained | 5/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1089C>A | p.Tyr363Ter | stop_gained | 5/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.18C>A | p.Tyr6Ter | stop_gained | 4/20 | 1 | |||
RECQL4 | ENST00000524998.1 | c.612C>A | p.Tyr204Ter | stop_gained | 3/4 | 3 | |||
RECQL4 | ENST00000532846.2 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247582Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134838
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459214Hom.: 0 Cov.: 66 AF XY: 0.00000689 AC XY: 5AN XY: 725628
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
RECQL4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2023 | Variant summary: RECQL4 c.1089C>A (p.Tyr363X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 247582 control chromosomes. To our knowledge, no occurrence of c.1089C>A in individuals affected with RECQL4-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Baller-Gerold syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change creates a premature translational stop signal (p.Tyr363*) in the RECQL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1070028). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at