NM_004329.3:c.1433G>T

Variant names:

• chr10-86923466-G-T
• rs113849804
• NM_004329.3:c.1433G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_004329.3(BMPR1A):​c.1433G>T​(p.Arg478Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,894 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R478C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.94
• Publications: 14 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 36 uncertain in NM_004329.3
• BP6: Variant 10-86923466-G-T is Benign according to our data. Variant chr10-86923466-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 628297.
• BS2: High AC in GnomAdExome4 at 19 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.1433G>T	p.Arg478Leu	missense	Exon 12 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.1508G>T	p.Arg503Leu	missense	Exon 13 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.1481G>T	p.Arg494Leu	missense	Exon 13 of 14	NP_001393489.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.1433G>T	p.Arg478Leu	missense	Exon 12 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.1481G>T	p.Arg494Leu	missense	Exon 13 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.1433G>T	p.Arg478Leu	missense	Exon 13 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251494 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.040	D
Polyphen		0.71	P
Vest4		0.57
MutPred		0.63		Loss of MoRF binding (P = 0.0132)
MVP		0.85
MPC		0.85
ClinPred		0.76	D
GERP RS		4.6
Varity_R		0.49
gMVP		0.77
Mutation Taster		=76/24	polymorphism

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: rs113849804; hg19: chr10-88683223;