rs56108371

Variant names:

• chr10-86917235-G-A
• rs56108371
• NM_004329.3:c.777G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-86917235-G-A
• chr10-86917235-G-T
• chr10-86917235-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004329.3(BMPR1A):​c.777G>A​(p.Ala259Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,613,860 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (14 hom.)
• Consequence: BMPR1A NM_004329.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.625
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-86917235-G-A is Benign according to our data. Variant chr10-86917235-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.625 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00198 (301/152242) while in subpopulation EAS AF = 0.00984 (51/5182). AF 95% confidence interval is 0.00769. There are 3 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 301 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.777G>A	p.Ala259Ala	synonymous	Exon 9 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.852G>A	p.Ala284Ala	synonymous	Exon 10 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.825G>A	p.Ala275Ala	synonymous	Exon 10 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.777G>A	p.Ala259Ala	synonymous	Exon 9 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.825G>A	p.Ala275Ala	synonymous	Exon 10 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.777G>A	p.Ala259Ala	synonymous	Exon 10 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152124 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000851 AC: 213 AN: 250416 AF XY: 0.000701

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00447

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000846 AC: 1237 AN: 1461618 Hom.: 14 Cov.: 32 AF XY: 0.000828 AC XY: 602 AN XY: 727102

African (AFR) AF: 0.00514 AC: 172 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0197 AC: 780 AN: 39692

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86238

European-Finnish (FIN) AF: 0.000656 AC: 35 AN: 53356

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1111864

Other (OTH) AF: 0.000812 AC: 49 AN: 60366

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152242 Hom.: 3 Cov.: 32 AF XY: 0.00198 AC XY: 147 AN XY: 74428

African (AFR) AF: 0.00522 AC: 217 AN: 41532

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00984 AC: 51 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000888 Hom.: 0

Bravo AF: 0.00201

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	Juvenile polyposis syndrome (4)
-	-	3	not provided (3)
-	-	1	Generalized juvenile polyposis/juvenile polyposis coli (1)
-	-	1	Juvenile polyposis syndrome;C1864730:Polyposis syndrome, hereditary mixed, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.8
DANN	Benign	0.73
PhyloP100		-0.63
Mutation Taster		=99/1	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: rs56108371; hg19: chr10-88676992;