rs750293380
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000057.4(BLM):c.98+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000628 in 1,591,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000057.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000130 AC: 3AN: 230636Hom.: 0 AF XY: 0.00000805 AC XY: 1AN XY: 124262
GnomAD4 exome AF: 0.00000625 AC: 9AN: 1439768Hom.: 0 Cov.: 30 AF XY: 0.00000838 AC XY: 6AN XY: 715722
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:4
This sequence change affects a donor splice site in intron 2 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs750293380, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of Bloom syndrome and it has also been observed in the heterozygous state in individuals affected with uterine corpus endometrial carcinoma, colorectal cancer, male breast cancer (PMID: 17407155, 26358404, 26689913, 30613976). ClinVar contains an entry for this variant (Variation ID: 371055). Studies have shown that disruption of this splice site results in exon 2 skipping and activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -
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NM_000057.2(BLM):c.98+1G>A is a canonical splice variant classified as likely pathogenic in the context of Bloom syndrome. c.98+1G>A has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. c.98+1G>A has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000057.2(BLM):c.98+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. -
not provided Pathogenic:1
Observed heterozygous in individuals with metastatic prostate cancer and early-onset colorectal cancer (PMID: 26358404, 31816118, 29439820); 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: 30613976, 17407155, 26689913, 26358404, 29439820, 31816118) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.98+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the BLM gene. This alteration has been reported in the heterozygous state in an individual with a personal history of early-onset colorectal cancer and a strong family history of colorectal cancer, as well as an individual with metastatic castration-resistant prostate cancer (de Voer RM et al. Sci Rep, 2015 Sep;5:14060; Antonarakis ES et al. Eur. Urol., 2018 08;74:218-225). Another alteration at this position (c.98+1G>T) has been reported in a compound heterozygous state in an individual diagnosed with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at