NM_004329.3:c.247_251delTTTGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004329.3(BMPR1A):​c.247_251delTTTGC​(p.Phe83HisfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

BMPR1A
NM_004329.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.98
Variant links:
Genes affected
BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 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. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-86892138-ATTGCT-A is Pathogenic according to our data. Variant chr10-86892138-ATTGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 188270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BMPR1ANM_004329.3 linkc.247_251delTTTGC p.Phe83HisfsTer6 frameshift_variant Exon 5 of 13 ENST00000372037.8 NP_004320.2 P36894

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BMPR1AENST00000372037.8 linkc.247_251delTTTGC p.Phe83HisfsTer6 frameshift_variant Exon 5 of 13 1 NM_004329.3 ENSP00000361107.2 P36894

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Juvenile polyposis syndrome Pathogenic:2
May 25, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jul 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 188270). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe83Hisfs*6) in the BMPR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). -

Generalized juvenile polyposis/juvenile polyposis coli Pathogenic:1
Feb 02, 2015
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change deletes 5 nucleotides in exon 5 of the BMPR1A mRNA (c.243_247delTTGCT), causing a frameshift at codon 83. This creates a premature translational stop signal (p.Phe83Hisfs*6) and is expected to result in an absent or disrupted protein product. While this particular sequence change has not been reported in the literature, truncating sequence changes in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513, 16152648). For these reasons, this sequence change has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs786204187; hg19: chr10-88651895; API