6-55874255-A-G

Variant names:

• chr6-55874255-A-G
• rs3798818
• NM_021073.4:c.490+121T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021073.4(BMP5):​c.490+121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 1,273,494 control chromosomes in the GnomAD database, including 1,833 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (196 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1637 hom.)
• Consequence: BMP5 NM_021073.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	NM_021073.4	MANE Select	c.490+121T>C		intron	N/A	NP_066551.1
	BMP5	NM_001329754.2		c.490+121T>C		intron	N/A	NP_001316683.1
	BMP5	NM_001329756.2		c.490+121T>C		intron	N/A	NP_001316685.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.490+121T>C		intron	N/A	ENSP00000359866.3

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5766 AN: 152062 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0364

GnomAD4 exome AF: 0.0452 AC: 50699 AN: 1121314 Hom.: 1637 AF XY: 0.0466 AC XY: 26519 AN XY: 568650

African (AFR) AF: 0.0113 AC: 288 AN: 25392

American (AMR) AF: 0.0609 AC: 2284 AN: 37510

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 566 AN: 22370

East Asian (EAS) AF: 0.180 AC: 6404 AN: 35574

South Asian (SAS) AF: 0.0836 AC: 6185 AN: 73972

European-Finnish (FIN) AF: 0.0248 AC: 1011 AN: 40748

Middle Eastern (MID) AF: 0.0505 AC: 181 AN: 3584

European-Non Finnish (NFE) AF: 0.0379 AC: 31592 AN: 833458

Other (OTH) AF: 0.0449 AC: 2188 AN: 48706

GnomAD4 genome AF: 0.0379 AC: 5771 AN: 152180 Hom.: 196 Cov.: 32 AF XY: 0.0386 AC XY: 2875 AN XY: 74402

African (AFR) AF: 0.0134 AC: 556 AN: 41572

American (AMR) AF: 0.0569 AC: 868 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.159 AC: 817 AN: 5152

South Asian (SAS) AF: 0.0911 AC: 440 AN: 4828

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2712 AN: 67974

Other (OTH) AF: 0.0380 AC: 80 AN: 2108

Alfa AF: 0.0403 Hom.: 528

Bravo AF: 0.0387

Asia WGS AF: 0.118 AC: 408 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.6
DANN	Benign	0.78
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs3798818; hg19: chr6-55739053;