rs786200889
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004260.4(RECQL4):c.3056-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RECQL4
NM_004260.4 splice_acceptor, intron
NM_004260.4 splice_acceptor, intron
Scores
2
2
Splicing: ADA: 0.003217
2
Clinical Significance
Conservation
PhyloP100: 0.340
Genes affected
RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-144512326-T-G is Pathogenic according to our data. Variant chr8-144512326-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.3056-2A>C | splice_acceptor_variant, intron_variant | ENST00000617875.6 | NP_004251.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.3056-2A>C | splice_acceptor_variant, intron_variant | 1 | NM_004260.4 | ENSP00000482313.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 35
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459684Hom.: 0 Cov.: 79 AF XY: 0.00000138 AC XY: 1AN XY: 726032
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74376
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Baller-Gerold syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2006 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change affects an acceptor splice site in intron 17 of the RECQL4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Baller-Gerold syndrome and/or breast cancer (PMID: 15964893, 33999380). This variant is also known as IVS17-2A>C. ClinVar contains an entry for this variant (Variation ID: 6075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34869606, 15964893) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 11, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | May 18, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Benign
D
GERP RS
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -20
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at