15-90747491-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000057.4(BLM):c.98+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00000625 in 1,439,768 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:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: BLM NM_000057.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.023742361 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-90747491-G-T is Pathogenic according to our data. Variant chr15-90747491-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.98+1G>T		splice_donor_variant		ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.98+1G>T		splice_donor_variant		1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000130 AC: 3 AN: 230636 Hom.: 0 AF XY: 0.0000161 AC XY: 2 AN XY: 124262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000625 AC: 9 AN: 1439768 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 4 AN XY: 715722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000684

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.0000505

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_000057.3(BLM):c.98+1G>T is a canonical splice site variant classified as likely pathogenic in the context of Bloom syndrome. c.98+1G>T has been observed in a case with relevant disease (PMID: 17407155). Functional assessments of this variant are available in the literature (PMID: 17407155). c.98+1G>T has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, NM_000057.3(BLM):c.98+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	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 disrupted protein product. This variant is present in population databases (rs750293380, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 370200). Studies have shown that disruption of this splice site results in exon 2 skipping and activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2021	Variant summary: BLM c.98+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. These predictions are supported by RT-PCR studies that showed exon 2 skipping, though the data was not available for review (German_2007). The variant allele was found at a frequency of 1.3e-05 in 230636 control chromosomes (gnomAD). c.98+1G>T has been reported in the literature in an individual affected with Bloom Syndrome (German_2007). A different variant at the same location (c.98+1G>A) has also been implicated in Bloom Syndrome. Four other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 05, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 28, 2023

The BLM c.98+1G>T variant disrupts a canonical splice-donor site and interferes with normal BLM mRNA splicing. This variant has been reported in the published literature in an individual with Bloom syndrome (PMID: 17407155 (2007)). It has also been seen in an individual with acute lymphoblastic leukemia (PMID: 34308104 (2021)). RNA analysis showed that the exon was skipped, which excludes the initiator methionine from the transcript, however further research is needed (PMID: 17407155 (2007)). The frequency of this variant in the general population, 0.000013 (3/230636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The c.98+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the BLM gene. This alteration has been reported in a compound heterozygous state with the Ashkenazi founder mutation (c.2207_2212delinsTAGATTC) in a child with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs750293380; hg19: chr15-91290721;