Genetic Variant BMP5:p.Phe305Leu (chr6-55774163-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_021073.4(BMP5):c.913T>C(p.Phe305Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

BMP5
NM_021073.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.71

Publications

2 publications found

Variant links:

Genes affected

BMP5 (HGNC:1072): (bone morphogenetic protein 5) 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. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

BMP5 Gene-Disease associations (from GenCC):

dysostosis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

BMP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMP5	NM_021073.4	MANE Select	c.913T>C	p.Phe305Leu	missense	Exon 4 of 7	NP_066551.1	P22003-1
BMP5	NM_001329754.2		c.913T>C	p.Phe305Leu	missense	Exon 4 of 6	NP_001316683.1	P22003-2
BMP5	NM_001329756.2		c.913T>C	p.Phe305Leu	missense	Exon 4 of 5	NP_001316685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.913T>C	p.Phe305Leu	missense	Exon 4 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.913T>C	p.Phe305Leu	missense	Exon 4 of 6	ENSP00000571582.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251270

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461148

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33430

American (AMR)

AF:

0.0000224

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1111514

Other (OTH)

AF:

0.0000994

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151948

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.6

PhyloP100

8.7

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.66

Sift

Uncertain

0.021

Sift4G

Benign

0.097

Polyphen

0.94

Vest4

0.88

MutPred

0.63

Loss of methylation at K306 (P = 0.0303)

MVP

0.88

MPC

0.66

ClinPred

0.69

GERP RS

5.7

Varity_R

0.67

gMVP

0.70

Mutation Taster

=14/86

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over