6-55759124-TACACACACACAC-TACACACACACACACACACACAC

Variant names:

• chr6-55759124-T-TACACACACAC
• rs749127959
• NM_021073.4:c.1105-19_1105-10dupGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_021073.4(BMP5):​c.1105-19_1105-10dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., cov: 18)
  • Exomes 𝑓: 0.013 (389 hom.)
• Consequence: BMP5 NM_021073.4 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.73
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-55759124-T-TACACACACAC is Benign according to our data. Variant chr6-55759124-T-TACACACACAC is described in ClinVar as Likely_benign. ClinVar VariationId is 3037354.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (848/54206) while in subpopulation NFE AF = 0.0229 (696/30458). AF 95% confidence interval is 0.0214. There are 32 homozygotes in GnomAd4. There are 347 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	NM_021073.4	MANE Select	c.1105-19_1105-10dupGTGTGTGTGT		intron	N/A	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1323_1104+1332dupGTGTGTGTGT		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3452_1028-3443dupGTGTGTGTGT		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.1105-10_1105-9insGTGTGTGTGT		intron	N/A	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1332_1104+1333insGTGTGTGTGT		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 847 AN: 54176 Hom.: 32 Cov.: 18

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.0369

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0171

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00136

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0152

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.00799

GnomAD2 exomes AF: 0.00263 AC: 562 AN: 213682 AF XY: 0.00256

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000851

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00402

GnomAD4 exome AF: 0.0132 AC: 5064 AN: 382918 Hom.: 389 Cov.: 0 AF XY: 0.0125 AC XY: 2715 AN XY: 216710

African (AFR) AF: 0.00245 AC: 27 AN: 11010

American (AMR) AF: 0.00374 AC: 132 AN: 35264

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 126 AN: 12666

East Asian (EAS) AF: 0.0000567 AC: 1 AN: 17624

South Asian (SAS) AF: 0.00365 AC: 214 AN: 58590

European-Finnish (FIN) AF: 0.0140 AC: 359 AN: 25730

Middle Eastern (MID) AF: 0.00147 AC: 3 AN: 2042

European-Non Finnish (NFE) AF: 0.0195 AC: 3928 AN: 201950

Other (OTH) AF: 0.0152 AC: 274 AN: 18042

GnomAD4 genome AF: 0.0156 AC: 848 AN: 54206 Hom.: 32 Cov.: 18 AF XY: 0.0145 AC XY: 347 AN XY: 23890

African (AFR) AF: 0.00297 AC: 41 AN: 13784

American (AMR) AF: 0.0136 AC: 41 AN: 3018

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 31 AN: 1812

East Asian (EAS) AF: 0.000563 AC: 1 AN: 1776

South Asian (SAS) AF: 0.00136 AC: 2 AN: 1466

European-Finnish (FIN) AF: 0.0153 AC: 10 AN: 652

Middle Eastern (MID) AF: 0.0152 AC: 1 AN: 66

European-Non Finnish (NFE) AF: 0.0229 AC: 696 AN: 30458

Other (OTH) AF: 0.00791 AC: 5 AN: 632

Alfa AF: 0.00756 Hom.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BMP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs749127959; hg19: chr6-55623922;