chr10-86876019-A-C

Variant names:

• chr10-86876019-A-C
• rs786203157
• NM_004329.3:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001406588.1(BMPR1A):​c.-79A>C variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000581498: Functional studies for this variant are conflicting with aberrant subcellular localization, intact bone morphogenetic protein (BMP) signaling, and reduced BMPR1A protein expression being demonstrated" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPR1A NM_001406588.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.97
• Publications: 12 publications found

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]

BMPR1A Gene-Disease associations (from GenCC):

• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• polyposis syndrome, hereditary mixed, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary mixed polyposis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000581498: Functional studies for this variant are conflicting with aberrant subcellular localization, intact bone morphogenetic protein (BMP) signaling, and reduced BMPR1A protein expression being demonstrated; however, BMPR1A protein may have failed to be detected due to a loss of the N-terminal portion of the protein with use of an alternate downstream start codon (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45).; SCV001351393: cells transfected with a construct containing this variant lacked the full-length BMPR1A protein product (PMID: 23433720).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-86876019-A-C is Pathogenic according to our data. Variant chr10-86876019-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 429102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406588.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 3 of 13	NP_004320.2
	BMPR1A	NM_001406588.1		c.-79A>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001393517.1
	BMPR1A	NM_001406559.1		c.1A>C	p.Met1?	initiator_codon	Exon 3 of 14	NP_001393488.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 3 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000713673.1		c.-137A>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	ENSP00000518975.1	A0AAQ5BGL1
	BMPR1A	ENST00000713670.1		c.-211A>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	ENSP00000518972.1	A0AAQ5BGQ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Juvenile polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.39	T
PhyloP100		6.0
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.96
MutPred		0.97		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.98
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.57
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786203157; hg19: chr10-88635776;