20-6773599-G-A

Variant names:

• chr20-6773599-G-A
• rs235764
• NM_001200.4:c.346+3127G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001200.4(BMP2):​c.346+3127G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,056 control chromosomes in the GnomAD database, including 7,576 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7576 hom., cov: 32)
• Consequence: BMP2 NM_001200.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.794
• Publications: 15 publications found

Genes affected

BMP2 (HGNC:1069): (bone morphogenetic protein 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

BMP2 Gene-Disease associations (from GenCC):

• short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• brachydactyly type A2

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001200.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	NM_001200.4	MANE Select	c.346+3127G>A		intron	N/A	NP_001191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	ENST00000378827.5	TSL:1 MANE Select	c.346+3127G>A		intron	N/A	ENSP00000368104.3

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46884 AN: 151936 Hom.: 7577 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.308 AC: 46889 AN: 152056 Hom.: 7576 Cov.: 32 AF XY: 0.302 AC XY: 22475 AN XY: 74328

African (AFR) AF: 0.390 AC: 16175 AN: 41454

American (AMR) AF: 0.272 AC: 4158 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1355 AN: 3470

East Asian (EAS) AF: 0.193 AC: 1001 AN: 5182

South Asian (SAS) AF: 0.221 AC: 1062 AN: 4810

European-Finnish (FIN) AF: 0.259 AC: 2734 AN: 10570

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19334 AN: 67976

Other (OTH) AF: 0.309 AC: 653 AN: 2110

Alfa AF: 0.293 Hom.: 24390

Bravo AF: 0.316

Asia WGS AF: 0.214 AC: 747 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.64
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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: rs235764; hg19: chr20-6754246;