chr15-90760191-CAC-TAT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000057.4(BLM):​c.1132_1134delinsTAT​(p.His378Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

BLM
NM_000057.4 missense

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.62
Variant links:
Genes affected
BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BLMNM_000057.4 linkuse as main transcriptc.1132_1134delinsTAT p.His378Tyr missense_variant 6/22 ENST00000355112.8 NP_000048.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BLMENST00000355112.8 linkuse as main transcriptc.1132_1134delinsTAT p.His378Tyr missense_variant 6/221 NM_000057.4 ENSP00000347232 P2

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bloom syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 17, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2021In 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BLM-related disease. This variant is reported as two separate single-nucleotide changes in population databases (c.1132C>T, ExAC 0.01% and c.1134C>T, ExAC 0.01%). However, in the read data for the 2 individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.1132_1134delinsTAT) and indicates that this variant is very likely present in the population databases at 0.01%. This sequence change replaces histidine with tyrosine at codon 378 of the BLM protein (p.His378Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 14, 2024The c.1132_1134delCACinsTAT variant (also known as p.H378Y), located in coding exon 5 of the BLM gene, results from an in-frame deletion of CAC and insertion of TAT at nucleotide positions 1132 to 1134. This results in the substitution of the histidine residue for a tyrosine residue at codon 378, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555419713; hg19: chr15-91303421; API