chr20-57173048-A-AT

Variant names:

• chr20-57173048-A-AT
• rs200005274
• NM_001719.3:c.1146+151dupA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001719.3(BMP7):​c.1146+151dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 741,768 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (3 hom.)
• Consequence: BMP7 NM_001719.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 20-57173048-A-AT is Benign according to our data. Variant chr20-57173048-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 1315742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 126 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP7	NM_001719.3	MANE Select	c.1146+151dupA		intron	N/A	NP_001710.1	A8K571

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP7	ENST00000395863.8	TSL:1 MANE Select	c.1146+151dupA		intron	N/A	ENSP00000379204.3	P18075
	BMP7	ENST00000450594.6	TSL:2	c.*58dupA		3_prime_UTR	Exon 6 of 6	ENSP00000398687.2	B1AL00
	BMP7	ENST00000395864.7	TSL:5	c.948+151dupA		intron	N/A	ENSP00000379205.3	B1AKZ9

Frequencies

GnomAD3 genomes AF: 0.000832 AC: 126 AN: 151454 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00284 AC: 1679 AN: 590202 Hom.: 3 Cov.: 8 AF XY: 0.00272 AC XY: 849 AN XY: 312706

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

African (AFR) AF: 0.00177 AC: 28 AN: 15792

American (AMR) AF: 0.00131 AC: 41 AN: 31362

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 25 AN: 18828

East Asian (EAS) AF: 0.000356 AC: 11 AN: 30862

South Asian (SAS) AF: 0.00127 AC: 76 AN: 59954

European-Finnish (FIN) AF: 0.0102 AC: 451 AN: 44376

Middle Eastern (MID) AF: 0.00178 AC: 5 AN: 2816

European-Non Finnish (NFE) AF: 0.00277 AC: 985 AN: 355434

Other (OTH) AF: 0.00185 AC: 57 AN: 30778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000831 AC: 126 AN: 151566 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74058

African (AFR) AF: 0.0000483 AC: 2 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00960 AC: 100 AN: 10418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67804

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00124 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31
Mutation Taster		=100/0	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: rs200005274; hg19: chr20-55748104; COSMIC: COSV101215635; COSMIC: COSV101215635;