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GeneBe

15-90747394-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000057.4(BLM):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000138 in 1,454,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BLM
NM_000057.4 start_lost

Scores

6
8
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.14
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 Pathogenic. Variant got 20 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000057.4 (BLM) was described as [Likely_pathogenic] in ClinVar as 558084
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-90747394-T-C is Pathogenic according to our data. Variant chr15-90747394-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BLMNM_000057.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/22 ENST00000355112.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BLMENST00000355112.8 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/221 NM_000057.4 P2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1454252
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
723026
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000181
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bloom syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylMar 02, 2016- -
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 12, 2023The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the BLM gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.26
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.38
T;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.0049
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;.
Vest4
0.85
MutPred
1.0
Loss of stability (P = 0.1629);Loss of stability (P = 0.1629);
MVP
0.86
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.76
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1057516593; hg19: chr15-91290624; COSMIC: COSV105267722; COSMIC: COSV105267722; API