chr8-144513108-CAT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004260.4(RECQL4):βc.2492_2493delβ(p.His831ArgfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,568,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. H831H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004260.4 frameshift
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.2492_2493del | p.His831ArgfsTer52 | frameshift_variant | 15/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.2492_2493del | p.His831ArgfsTer52 | frameshift_variant | 15/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.1421_1422del | p.His474ArgfsTer52 | frameshift_variant | 14/20 | 1 | |||
ENST00000580385.1 | n.271+272_271+273del | intron_variant, non_coding_transcript_variant | 3 | ||||||
RECQL4 | ENST00000534626.6 | c.663_664del | p.His222ArgfsTer52 | frameshift_variant | 6/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000330 AC: 5AN: 151338Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000769 AC: 16AN: 208088Hom.: 0 AF XY: 0.0000621 AC XY: 7AN XY: 112668
GnomAD4 exome AF: 0.0000635 AC: 90AN: 1417210Hom.: 0 AF XY: 0.0000544 AC XY: 38AN XY: 699038
GnomAD4 genome AF: 0.0000330 AC: 5AN: 151450Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 2AN XY: 74000
ClinVar
Submissions by phenotype
Baller-Gerold syndrome Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Aug 10, 2022 | The c.2492_2493del;p.(His831Argfs*52) is a null frameshift variant (NMD) in the RECQL4 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 6064; OMIM: 603780.0003; PMID: 28486640; 24518840; 19291770) - PS4. The variant is present at low allele frequencies population databases (rs752729755 β gnomAD 0.0003304%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(His831Argfs*52) was detected in trans with a pathogenic variant (PMID: 28486640; 24518840; 19291770) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24518840) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.His831Argfs*52) 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 (rs752729755, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of RECQL4-related conditions (PMID: 10319867, 19291770, 24518840, 28486640). ClinVar contains an entry for this variant (Variation ID: 6064). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10319867, 24518840, 29478780, 29462647, 19291770, 31604778, 29625052, 31589614, 33294214, 32482547, 33077847, 28486640) - |
Rapadilino syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 26, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
Rothmund-Thomson syndrome type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 1998 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at