chr10-86912327-A-G

Variant names:

• chr10-86912327-A-G
• rs55992440
• NM_004329.3:c.618A>G

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.618A>G​(p.Leu206Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,040 control chromosomes in the GnomAD database, including 2 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. L206L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: BMPR1A NM_004329.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.268
• Publications: 3 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=-0.47).
• BP6: Variant 10-86912327-A-G is Benign according to our data. Variant chr10-86912327-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00231 (352/152310) while in subpopulation AFR AF = 0.00808 (336/41564). AF 95% confidence interval is 0.00737. There are 1 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 352 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.618A>G	p.Leu206Leu	synonymous	Exon 8 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.693A>G	p.Leu231Leu	synonymous	Exon 9 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.666A>G	p.Leu222Leu	synonymous	Exon 9 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.618A>G	p.Leu206Leu	synonymous	Exon 8 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.666A>G	p.Leu222Leu	synonymous	Exon 9 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.618A>G	p.Leu206Leu	synonymous	Exon 9 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.00143

GnomAD2 exomes AF: 0.000641 AC: 161 AN: 251360 AF XY: 0.000434

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000213 AC: 312 AN: 1461730 Hom.: 1 Cov.: 31 AF XY: 0.000187 AC XY: 136 AN XY: 727162

African (AFR) AF: 0.00747 AC: 250 AN: 33472

American (AMR) AF: 0.000671 AC: 30 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111954

Other (OTH) AF: 0.000447 AC: 27 AN: 60384

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74494

African (AFR) AF: 0.00808 AC: 336 AN: 41564

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.00252

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Juvenile polyposis syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.0
DANN	Benign	0.79
PhyloP100		-0.27
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: rs55992440; hg19: chr10-88672084;