rs748943489
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000057.4(BLM):c.3970C>T(p.His1324Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000057.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135896
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1324 of the BLM protein (p.His1324Tyr). This variant is present in population databases (rs748943489, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Bloom syndrome (PMID: 17407155, 31159747). ClinVar contains an entry for this variant (Variation ID: 454145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 17407155). 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. | Sep 16, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2022 | The p.H1324Y variant (also known as c.3970C>T), located in coding exon 20 of the BLM gene, results from a C to T substitution at nucleotide position 3970. The histidine at codon 1324 is replaced by tyrosine, an amino acid with similar properties. This variant has been identified in one person with Bloom Syndrome and functional studies have shown that it preserves normal BLM protein function in reducing the levels of sister-chromatid exchanges in patient-derived cells (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Perreault-Micale C et al. Mol Genet Genomic Med, 2015 Jul;3:363-73). Another study determined that this variant (reported as c.3970C>T, p.H1324T) was not sensitive to the DNA damaging agent, hydroxyurea, similar to wildtype (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This variant was also reported as a variant of unknown signifcance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing genetic testing for hereditary cancer predisposition and in an individual with Bloom syndrome in published literature (German 2007, Tsaousis 2019); Published functional studies suggest no damaging effect: reduced levels of sister-chromatid exchanges (German 2007); This variant is associated with the following publications: (PMID: 26247052, 31159747, 17407155) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at