6-55759089-G-C

Variant names:

• chr6-55759089-G-C
• rs184900087
• NM_021073.4:c.1131C>G

Variant summary

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

The NM_021073.4(BMP5):​c.1131C>G​(p.Tyr377*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000878 in 113,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y377Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000088 (0 hom., cov: 28)
• Consequence: BMP5 NM_021073.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 0 publications found

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

ACMG classification

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

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	NM_021073.4	MANE Select	c.1131C>G	p.Tyr377*	stop_gained	Exon 6 of 7	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1368C>G		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3407C>G		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>G	p.Tyr377*	stop_gained	Exon 6 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1368C>G		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.00000878 AC: 1 AN: 113954 Hom.: 0 Cov.: 28

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000165

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000878 AC: 1 AN: 113954 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 51928

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

African (AFR) AF: 0.00 AC: 0 AN: 29502

American (AMR) AF: 0.00 AC: 0 AN: 7950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3232

East Asian (EAS) AF: 0.00 AC: 0 AN: 3440

South Asian (SAS) AF: 0.00 AC: 0 AN: 3402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 138

European-Non Finnish (NFE) AF: 0.0000165 AC: 1 AN: 60472

Other (OTH) AF: 0.00 AC: 0 AN: 1504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.1
Vest4		0.89
GERP RS		0.39
Mutation Taster		=25/175	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 26

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

Other links and lift over

dbSNP: rs184900087; hg19: chr6-55623887;