20-57183780-G-T

Variant names:

• chr20-57183780-G-T
• rs540533068
• NM_001719.3:c.900C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001719.3(BMP7):​c.900C>A​(p.Ser300Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BMP7 NM_001719.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• Publications: 1 publications found

Genes affected

BMP7 (HGNC:1074): (bone morphogenetic protein 7) 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, kidney and brown adipose tissue development. Additionally, this protein induces ectopic bone formation and may promote fracture healing in human patients. [provided by RefSeq, Jul 2016]

BMP7 Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hypospadias

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105293214).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001719.3. 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
	BMP7	NM_001719.3	MANE Select	c.900C>A	p.Ser300Arg	missense	Exon 4 of 7	NP_001710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP7	ENST00000395863.8	TSL:1 MANE Select	c.900C>A	p.Ser300Arg	missense	Exon 4 of 7	ENSP00000379204.3
	BMP7	ENST00000450594.6	TSL:2	c.900C>A	p.Ser300Arg	missense	Exon 4 of 6	ENSP00000398687.2
	BMP7	ENST00000433911.1	TSL:5	c.663C>A	p.Ser221Arg	missense	Exon 5 of 7	ENSP00000390814.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251466 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.62
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.68	T
Sift4G	Benign	0.68	T
Polyphen		0.062	B
Vest4		0.44
MutPred		0.31		Loss of phosphorylation at S300 (P = 0.0072)
MVP		0.52
MPC		0.76
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.36
gMVP		0.57
Mutation Taster		=79/21	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: rs540533068; hg19: chr20-55758836;