NM_000057.4:c.98+1G>C
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>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000138 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: 0.0000260 AC: 6AN: 230636Hom.: 0 AF XY: 0.0000402 AC XY: 5AN XY: 124262
GnomAD4 exome AF: 0.0000146 AC: 21AN: 1439768Hom.: 0 Cov.: 30 AF XY: 0.0000196 AC XY: 14AN 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:5
Criteria applied: PVS1_MOD,PP1_MOD,PS1_SUP,PM2_SUP -
The c.98+1G>C variant in BLM has not been reported individuals with Bloom syndro me, but another variant at the same nucleotide position (c.98+1G>T) has been rep orted in the compound heterozygous state in 1 individual with Bloom syndrome (Ge rman 2007). A third variant at this nucleotide position (c.98+1G>A) has been rep orted to segregate with cancer risk in a single pedigree (de Voer 2015). This va riant has been identified in 7/113042 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750293380). Thi s variant occurs in the invariant region (+/- 1/2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BLM gene is an established disease mechanism in autosomal recessive Bloom syndrome. In summary, the c.98+1G>C variant meets cri teria to be classified as pathogenic for Bloom syndrome in an autosomal recessiv e manner. ACMG/AMP criteria applied: PVS1_Strong, PM5, PM2 -
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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 0.006%). Disruption of this splice site has been observed in individual(s) with Bloom syndrome, colorectal cancer, endometrial cancer, and/or prostate cancer (PMID: 17407155, 26358404, 26689913, 29439820). ClinVar contains an entry for this variant (Variation ID: 667391). 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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not provided Pathogenic:2
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); Observed in individuals with colorectal cancer, male breast cancer, ovarian cancer, and endometrial cancer (de Voer 2015, Lu 2015, Koczkowska 2018, Rizzolo 2019); This variant is associated with the following publications: (PMID: 26689913, 26358404, 30441849, 30613976) -
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BLM-related disorder Pathogenic:1
The BLM c.98+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in BLM associated disorders. This variant is reported in 0.0061% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/667391/). Variants that disrupt the consensus splice donor site in BLM are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.98+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the BLM gene. This nucleotide position is highly conserved in available vertebrate species. Another alteration at this position (c.98+1G>T) has been reported in a compound heterozygous state in an individual with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). Additionally, another alteration at this position (c.98+1G>A) has been reported in a heterozygous state in an individual with a personal history of early-onset colorectal cancer and a strong family history of colorectal cancer (deVoer RM et al. Sci. Rep. 2015 Sep;5:14060). 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