rs1555420546

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000355112.8(BLM):​c.2194A>T​(p.Ile732Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,090 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 predict no significant impact on normal splicing. 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. I732M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

BLM
ENST00000355112.8 missense, splice_region

Scores

6
9
4
Splicing: ADA: 0.6589
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 8.55
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000355112.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BLMNM_000057.4 linkuse as main transcriptc.2194A>T p.Ile732Phe missense_variant, splice_region_variant 10/22 ENST00000355112.8 NP_000048.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BLMENST00000355112.8 linkuse as main transcriptc.2194A>T p.Ile732Phe missense_variant, splice_region_variant 10/221 NM_000057.4 ENSP00000347232 P2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.07e-7
AC:
1
AN:
1415090
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
706242
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:
0.00
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bloom syndrome Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jun 25, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 05, 2022This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 732 of the BLM protein (p.Ile732Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 524776). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.016
D;D
Sift4G
Uncertain
0.039
D;D
Polyphen
0.99
D;.
Vest4
0.97
MutPred
0.56
Gain of catalytic residue at I732 (P = 0.0229);Gain of catalytic residue at I732 (P = 0.0229);
MVP
0.89
MPC
0.57
ClinPred
0.98
D
GERP RS
5.7
Varity_R
0.75
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.66
dbscSNV1_RF
Benign
0.52
SpliceAI score (max)
0.030
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: rs1555420546; hg19: chr15-91310140; API