4-94996135-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PVS1PP3_StrongBP6_Moderate
The NM_001203.3(BMPR1B):c.-18+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.0000591 in 152,202 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Consequence
BMPR1B
NM_001203.3 splice_donor
NM_001203.3 splice_donor
Scores
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.40
Genes affected
BMPR1B (HGNC:1077): (bone morphogenetic protein receptor type 1B) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are BMPs, which are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. Mutations in this gene have been associated with primary pulmonary hypertension. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 4-94996135-G-T is Benign according to our data. Variant chr4-94996135-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 906581.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR1B | NM_001203.3 | c.-18+1G>T | splice_donor_variant | ENST00000515059.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1B | ENST00000515059.6 | c.-18+1G>T | splice_donor_variant | 1 | NM_001203.3 | P4 | |||
BMPR1B | ENST00000506363.5 | c.-18+1G>T | splice_donor_variant | 4 | |||||
BMPR1B | ENST00000509540.6 | c.-18+1G>T | splice_donor_variant | 2 | P4 | ||||
BMPR1B | ENST00000672698.1 | c.-18+1G>T | splice_donor_variant | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152202Hom.: 0 Cov.: 32
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74358
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Brachydactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 02, 2017 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at