rs200364297
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000057.4(BLM):c.1087G>A(p.Ala363Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A363V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000057.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.1087G>A | p.Ala363Thr | missense_variant, splice_region_variant | 5/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.1087G>A | p.Ala363Thr | missense_variant, splice_region_variant | 5/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000799 AC: 20AN: 250172Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135282
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461356Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 726998
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74298
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 363 of the BLM protein (p.Ala363Thr). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200364297, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 454062). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 06, 2022 | The BLM c.1087G>A (p.Ala363Thr) missense change has a maximum subpopulation frequency of 0.088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/15-91298168-G-A). This variant is located adjacent to the donor splice site of intron 5. This variant is predicted to result in loss of the native splice donor site (PP3) and skipping of exon 5 has been confirmed by RNA studies (PS3_supporting; internal data). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3_supporting, PP3. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2024 | The p.A363T variant (also known as c.1087G>A), located in coding exon 4 of the BLM gene, results from a G to A substitution at nucleotide position 1087. The amino acid change results in alanine to threonine at codon 363, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at