rs1064792985

Variant names:

• chr10-86890202-GATGCTATTAATAACAC-G
• rs1064792985
• NM_004329.3:c.213_228delTATTAATAACACATGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_004329.3(BMPR1A):​c.213_228delTATTAATAACACATGC​(p.Ile72fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A71A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR1A NM_004329.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.37
• Publications: 0 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: Ambry Genetics, Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-86890202-GATGCTATTAATAACAC-G is Pathogenic according to our data. Variant chr10-86890202-GATGCTATTAATAACAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 411600.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 4 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 4 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 4 of 14	NP_001393489.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 4 of 13	ENSP00000361107.2
	BMPR1A	ENST00000480152.3	TSL:3	c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 5 of 14	ENSP00000483569.2
	BMPR1A	ENST00000713672.1		c.213_228delTATTAATAACACATGC	p.Ile72fs	frameshift splice_region	Exon 3 of 12	ENSP00000518974.1

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Juvenile polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064792985; hg19: chr10-88649959;