chr15-90760983-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000057.4(BLM):​c.1610C>T​(p.Thr537Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T537N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0710

Publications

0 publications found
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]
BLM Gene-Disease associations (from GenCC):
  • Bloom syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
  • osteosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • breast cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05810964).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLMNM_000057.4 linkc.1610C>T p.Thr537Ile missense_variant Exon 7 of 22 ENST00000355112.8 NP_000048.1 P54132

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLMENST00000355112.8 linkc.1610C>T p.Thr537Ile missense_variant Exon 7 of 22 1 NM_000057.4 ENSP00000347232.3 P54132

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460184
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726366
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33286
American (AMR)
AF:
0.00
AC:
0
AN:
44314
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.0000117
AC:
1
AN:
85820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53378
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111574
Other (OTH)
AF:
0.00
AC:
0
AN:
60298
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 26, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.T537I variant (also known as c.1610C>T), located in coding exon 6 of the BLM gene, results from a C to T substitution at nucleotide position 1610. The threonine at codon 537 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
8.2
DANN
Benign
0.90
DEOGEN2
Benign
0.070
T;.
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.068
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.058
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.76
N;.
PhyloP100
-0.071
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.063
Sift
Benign
0.41
T;T
Sift4G
Benign
0.52
T;T
Polyphen
0.013
B;.
Vest4
0.056
MutPred
0.23
Loss of glycosylation at T537 (P = 0.0424);Loss of glycosylation at T537 (P = 0.0424);
MVP
0.66
MPC
0.095
ClinPred
0.018
T
GERP RS
-0.71
Varity_R
0.034
gMVP
0.35
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs1555419928; hg19: chr15-91304213; API