20-57173048-A-ATT

Variant names:

• chr20-57173048-A-ATT
• rs200005274
• NM_001719.3:c.1146+150_1146+151dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001719.3(BMP7):​c.1146+150_1146+151dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000335 in 596,690 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BMP7 NM_001719.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP7	NM_001719.3	c.1146+150_1146+151dupAA		intron_variant	Intron 6 of 6	ENST00000395863.8	NP_001710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP7	ENST00000395863.8	c.1146+150_1146+151dupAA		intron_variant	Intron 6 of 6	1	NM_001719.3	ENSP00000379204.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000335 AC: 2 AN: 596690 Hom.: 0 Cov.: 8 AF XY: 0.00000316 AC XY: 1 AN XY: 316172

⚠️ 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: 15950

American (AMR) AF: 0.00 AC: 0 AN: 31736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19074

East Asian (EAS) AF: 0.00 AC: 0 AN: 31122

South Asian (SAS) AF: 0.00 AC: 0 AN: 60600

European-Finnish (FIN) AF: 0.0000223 AC: 1 AN: 44794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00000278 AC: 1 AN: 359502

Other (OTH) AF: 0.00 AC: 0 AN: 31076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200005274; hg19: chr20-55748104;