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GeneBe

15-90747393-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000057.4(BLM):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000688 in 1,453,778 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BLM
NM_000057.4 start_lost

Scores

6
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.83
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 12 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 370566
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BLMNM_000057.4 linkuse as main transcriptc.1A>G 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.1A>G p.Met1? start_lost 2/221 NM_000057.4 P2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453778
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
722816
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bloom syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 25, 2023In 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BLM mRNA. The next in-frame methionine is located at codon 157. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
-0.028
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Benign
-1.8
N;N
REVEL
Uncertain
0.54
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.96
P;.
Vest4
0.81
MutPred
0.99
Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP
0.89
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.76
gMVP
0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-91290623; API