rs1005464

Variant names:

• chr20-6775501-G-A
• rs1005464
• NM_001200.4:c.347-2744G>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.347-2744G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 151,904 control chromosomes in the GnomAD database, including 3,264 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 0.20 (3264 hom., cov: 32)
• Consequence: BMP2 NM_001200.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499
• Publications: 38 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.349 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	NM_001200.4	MANE Select	c.347-2744G>A		intron	N/A	NP_001191.1	P12643

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	ENST00000378827.5	TSL:1 MANE Select	c.347-2744G>A		intron	N/A	ENSP00000368104.3	P12643
	BMP2	ENST00000936876.1		c.347-2744G>A		intron	N/A	ENSP00000606935.1
	BMP2	ENST00000953442.1		c.347-2744G>A		intron	N/A	ENSP00000623501.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29940 AN: 151786 Hom.: 3258 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.197 AC: 29959 AN: 151904 Hom.: 3264 Cov.: 32 AF XY: 0.199 AC XY: 14795 AN XY: 74232

African (AFR) AF: 0.109 AC: 4497 AN: 41434

American (AMR) AF: 0.218 AC: 3324 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1865 AN: 5138

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4804

European-Finnish (FIN) AF: 0.226 AC: 2386 AN: 10552

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15009 AN: 67924

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.217 Hom.: 7993

Bravo AF: 0.192

Asia WGS AF: 0.253 AC: 878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.53
PhyloP100		0.50
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: rs1005464; hg19: chr20-6756148;