15-90749594-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000057.4(BLM):​c.326C>G​(p.Pro109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.200
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12172967).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BLMNM_000057.4 linkuse as main transcriptc.326C>G p.Pro109Arg missense_variant 3/22 ENST00000355112.8 NP_000048.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BLMENST00000355112.8 linkuse as main transcriptc.326C>G p.Pro109Arg missense_variant 3/221 NM_000057.4 ENSP00000347232 P2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461822
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727202
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:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bloom syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2023This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 109 of the BLM protein (p.Pro109Arg). 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: 524801). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 01, 2022The p.P109R variant (also known as c.326C>G), located in coding exon 2 of the BLM gene, results from a C to G substitution at nucleotide position 326. The proline at codon 109 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
12
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.081
N
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.7
N;N
REVEL
Benign
0.075
Sift
Uncertain
0.0060
D;D
Sift4G
Benign
0.47
T;T
Polyphen
0.84
P;.
Vest4
0.19
MutPred
0.43
Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP
0.82
MPC
0.14
ClinPred
0.26
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.088
gMVP
0.10

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: rs1555418317; hg19: chr15-91292824; API