rs142454490

chr10-86890092-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 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. 14/21 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:6 B:4
• Conservation: PhyloP100: 5.39

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a topological_domain Extracellular (size 128) in uniprot entity BMR1A_HUMAN there are 20 pathogenic changes around while only 2 benign (91%) in NM_004329.3
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• 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 id is 411623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.98C>G	p.Thr33Ser	missense_variant	4/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.98C>G	p.Thr33Ser	missense_variant	4/13	1	NM_004329.3	P1

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

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251344 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135832

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 SAS 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

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 25186627) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

BMPR1A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2022

The BMPR1A c.98C>G variant is predicted to result in the amino acid substitution p.Thr33Ser. This variant has been reported as probably benign in an individual with neuroblastoma (Table S4a - Zhang et al. 2015. PubMed ID: 26580448) and as a variant of uncertain significance in an individual with breast cancer (supporting data - Tung et al. 2014. PubMed ID: 25186627). This variant is present in 0.060% alleles in the gnomAD database (https://gnomad.broadinstitute.org/variant/chr10-88649849-C-G) and has conflicting interpretations in ClinVar of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/411623/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BMPR1A p.Thr33Ser variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (rs142454490) as “with other allele” and ClinVar (classified as uncertain significance by Invitae and Color and likely benign by Ambry Genetics). The variant was identified in control databases in 16 of 277,094 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 15 of 24,036 chromosomes (freq: 0.0006), Other in 1 of 6462 chromosomes (freq: 0.0002), but not in the Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Thr33Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Juvenile polyposis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.28
Sift	Benign	0.56	T;.
Sift4G	Benign	0.40	T;D
Polyphen		0.016	B;.
Vest4		0.34
MutPred		0.18		Gain of disorder (P = 0.0436);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs142454490; hg19: chr10-88649849;