dbSNP rs184900087: BMP5:p.Tyr377Tyr (chr6-55759089-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_021073.4(BMP5):c.1131C>T(p.Tyr377Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,362,090 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00068 ( 10 hom. )

Consequence

BMP5
NM_021073.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.14

Publications

0 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 6-55759089-G-A is Benign according to our data. Variant chr6-55759089-G-A is described in ClinVar as Benign. ClinVar VariationId is 3042737.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=1.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000677 (845/1248102) while in subpopulation AMR AF = 0.0183 (702/38360). AF 95% confidence interval is 0.0172. There are 10 homozygotes in GnomAdExome4. There are 342 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

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.1131C>T	p.Tyr377Tyr	synonymous	Exon 6 of 7	NP_066551.1	P22003-1
BMP5	NM_001329754.2		c.1104+1368C>T		intron	N/A	NP_001316683.1	P22003-2
BMP5	NM_001329756.2		c.1028-3407C>T		intron	N/A	NP_001316685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.1131C>T	p.Tyr377Tyr	synonymous	Exon 6 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1368C>T		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

118

AN:

113954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000373

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0119

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:

0.000132

Gnomad OTH

AF:

0.00266

GnomAD2 exomes

AF:

0.00246

AC:

614

AN:

249464

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.000677

AC:

845

AN:

1248102

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

342

AN XY:

618612

show subpopulations

African (AFR)

AF:

0.000219

AC:

AN:

27376

American (AMR)

AF:

0.0183

AC:

702

AN:

38360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18360

East Asian (EAS)

AF:

0.000100

AC:

AN:

19950

South Asian (SAS)

AF:

0.000107

AC:

AN:

84354

European-Finnish (FIN)

AF:

0.0000290

AC:

AN:

34506

Middle Eastern (MID)

AF:

0.000645

AC:

AN:

4648

European-Non Finnish (NFE)

AF:

0.0000780

AC:

AN:

974216

Other (OTH)

AF:

0.000993

AC:

AN:

46332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00104

AC:

118

AN:

113988

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

51946

show subpopulations

African (AFR)

AF:

0.000372

AC:

AN:

29536

American (AMR)

AF:

0.0119

AC:

AN:

7960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3232

East Asian (EAS)

AF:

0.00

AC:

AN:

3438

South Asian (SAS)

AF:

0.00

AC:

AN:

3390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

60474

Other (OTH)

AF:

0.00265

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000519

Hom.:

Asia WGS

AF:

0.00231

AC:

AN:

3468

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

BMP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.1

(source)

DANN

Benign

0.86

PhyloP100

1.1

Mutation Taster

=92/8

polymorphism

(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

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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