rs1555420546
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000057.4(BLM):c.2194A>T(p.Ile732Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,090 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000057.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.2194A>T | p.Ile732Phe | missense_variant, splice_region_variant | 10/22 | ENST00000355112.8 | NP_000048.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.2194A>T | p.Ile732Phe | missense_variant, splice_region_variant | 10/22 | 1 | NM_000057.4 | ENSP00000347232.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.07e-7 AC: 1AN: 1415090Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 706242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 05, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 732 of the BLM protein (p.Ile732Phe). This variant is not present in population databases (gnomAD no frequency). 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: 524776). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 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. | Jun 25, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2024 | The p.I732F variant (also known as c.2194A>T) is located in coding exon 9 of the BLM gene. The isoleucine at codon 732 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 9. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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