rs142454490

Variant names:

• chr10-86890092-C-G
• rs142454490
• NM_004329.3:c.98C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86890092-C-G
• chr10-86890092-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004329.3(BMPR1A):​c.98C>G​(p.Thr33Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. T33A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 5.39
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033703208).
• BP6: Variant 10-86890092-C-G is Benign according to our data. Variant chr10-86890092-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411623.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000131 (20/152306) while in subpopulation AFR AF = 0.000481 (20/41558). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 Unknown,AD 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.98C>G	p.Thr33Ser	missense	Exon 4 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.98C>G	p.Thr33Ser	missense	Exon 4 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.98C>G	p.Thr33Ser	missense	Exon 4 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.98C>G	p.Thr33Ser	missense	Exon 4 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.98C>G	p.Thr33Ser	missense	Exon 4 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.98C>G	p.Thr33Ser	missense	Exon 5 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251344 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000431

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: 0.000163

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461236 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726934

African (AFR) AF: 0.000598 AC: 20 AN: 33458

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74472

African (AFR) AF: 0.000481 AC: 20 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000378 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	-	2	Juvenile polyposis syndrome (2)
-	1	1	not specified (2)
-	1	-	BMPR1A-related disorder (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.047
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.28
Sift	Benign	0.56	T
Sift4G	Benign	0.40	T
Polyphen		0.016	B
Vest4		0.34
MutPred		0.18		Gain of disorder (P = 0.0436)
MVP		0.47
MPC		0.60
ClinPred		0.063	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.67
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142454490; hg19: chr10-88649849;