NM_004260.4:c.1390+2delT
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_004260.4(RECQL4):c.1390+2delT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,612,378 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_004260.4 splice_donor, intron
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_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1390+2delT | splice_donor_variant, intron_variant | Intron 7 of 20 | 1 | NM_004260.4 | ENSP00000482313.2 | |||
RECQL4 | ENST00000621189.4 | c.319+2delT | splice_donor_variant, intron_variant | Intron 6 of 19 | 1 | ENSP00000483145.1 | ||||
RECQL4 | ENST00000532846.2 | c.274+2delT | splice_donor_variant, intron_variant | Intron 3 of 8 | 5 | ENSP00000476551.1 | ||||
RECQL4 | ENST00000688394.1 | n.413+2delT | splice_donor_variant, intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes AF: 0.000394 AC: 60AN: 152250Hom.: 0 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.000389 AC: 96AN: 246886 AF XY: 0.000424 show subpopulations
GnomAD4 exome AF: 0.000145 AC: 211AN: 1460010Hom.: 1 Cov.: 33 AF XY: 0.000138 AC XY: 100AN XY: 726222 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000394 AC: 60AN: 152368Hom.: 0 Cov.: 34 AF XY: 0.000617 AC XY: 46AN XY: 74510 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Rapadilino syndrome Pathogenic:2
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Baller-Gerold syndrome Pathogenic:1
This sequence change affects a splice site in intron 7 of the RECQL4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs386833843, gnomAD 0.4%). Disruption of this splice site has been observed in individual(s) with RAPADILINO syndrome (PMID: 12952869, 18716613). It is commonly reported in individuals of Finnish ancestry (PMID: 12952869, 18716613). This variant is also known as IVS7+2delT. ClinVar contains an entry for this variant (Variation ID: 56398). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects RECQL4 function (PMID: 17250975, 22885111). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 12952869, 22885111). 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