rs35572415

Variant names:

• chr10-86919443-C-T
• rs35572415
• NM_004329.3:c.1140C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001406559.1(BMPR1A):​c.1215C>T​(p.Asp405Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,362 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.019 (323 hom.)
• Consequence: BMPR1A NM_001406559.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.03
• Publications: 12 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-86919443-C-T is Benign according to our data. Variant chr10-86919443-C-T is described in ClinVar as Benign. ClinVar VariationId is 132691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.015 (2285/152250) while in subpopulation AMR AF = 0.0242 (371/15302). AF 95% confidence interval is 0.0222. There are 24 homozygotes in GnomAd4. There are 1086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2285 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406559.1. 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.1140C>T	p.Asp380Asp	synonymous	Exon 10 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.1215C>T	p.Asp405Asp	synonymous	Exon 11 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.1188C>T	p.Asp396Asp	synonymous	Exon 11 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.1140C>T	p.Asp380Asp	synonymous	Exon 10 of 13	ENSP00000361107.2
	BMPR1A	ENST00000926286.1		c.1188C>T	p.Asp396Asp	synonymous	Exon 11 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.1140C>T	p.Asp380Asp	synonymous	Exon 11 of 14	ENSP00000483569.2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2287 AN: 152132 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0146 AC: 3665 AN: 251006 AF XY: 0.0152

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0192 AC: 27985 AN: 1461112 Hom.: 323 Cov.: 32 AF XY: 0.0189 AC XY: 13731 AN XY: 726878

African (AFR) AF: 0.00314 AC: 105 AN: 33454

American (AMR) AF: 0.0158 AC: 708 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 355 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00779 AC: 672 AN: 86230

European-Finnish (FIN) AF: 0.00642 AC: 343 AN: 53420

Middle Eastern (MID) AF: 0.0321 AC: 171 AN: 5320

European-Non Finnish (NFE) AF: 0.0221 AC: 24553 AN: 1111816

Other (OTH) AF: 0.0178 AC: 1075 AN: 60324

GnomAD4 genome AF: 0.0150 AC: 2285 AN: 152250 Hom.: 24 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74430

African (AFR) AF: 0.00407 AC: 169 AN: 41552

American (AMR) AF: 0.0242 AC: 371 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1524 AN: 67994

Other (OTH) AF: 0.0246 AC: 52 AN: 2110

Alfa AF: 0.0169 Hom.: 15

Bravo AF: 0.0168

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0248

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Juvenile polyposis syndrome (3)
-	-	3	not provided (3)
-	-	1	Generalized juvenile polyposis/juvenile polyposis coli (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.7
DANN	Benign	0.52
PhyloP100		1.0
Mutation Taster		=94/6	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: rs35572415; hg19: chr10-88679200;