chr20-6770143-G-T

Variant names:

• chr20-6770143-G-T
• rs974052081
• NM_001200.4:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001200.4(BMP2):​c.17G>T​(p.Arg6Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,401,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMP2 NM_001200.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.43
• Publications: 0 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

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.17G>T	p.Arg6Leu	missense	Exon 2 of 3	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.17G>T	p.Arg6Leu	missense	Exon 2 of 3	ENSP00000368104.3	P12643
	BMP2	ENST00000936876.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 2	ENSP00000606935.1
	BMP2	ENST00000953442.1		c.17G>T	p.Arg6Leu	missense	Exon 2 of 3	ENSP00000623501.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401000 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 691260

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32066

American (AMR) AF: 0.00 AC: 0 AN: 37554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 36534

South Asian (SAS) AF: 0.00 AC: 0 AN: 80132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1081204

Other (OTH) AF: 0.00 AC: 0 AN: 58098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.80	T
Polyphen		0.48	P
Vest4		0.70
MutPred		0.62		Gain of helix (P = 0.0325)
MVP		0.83
MPC		0.56
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.63
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs974052081; hg19: chr20-6750790;