chr6-55759124-T-TACAC

Variant names:

• chr6-55759124-T-TACAC
• rs749127959
• NM_021073.4:c.1105-13_1105-10dupGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_021073.4(BMP5):​c.1105-13_1105-10dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (110 hom., cov: 18)
  • Exomes 𝑓: 0.023 (451 hom.)
• Consequence: BMP5 NM_021073.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0288 (1561/54198) while in subpopulation EAS AF = 0.0377 (67/1776). AF 95% confidence interval is 0.0345. There are 110 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 110 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.1105-13_1105-10dupGTGT		intron	N/A	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1329_1104+1332dupGTGT		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3446_1028-3443dupGTGT		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_1105-9insGTGT		intron	N/A	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1332_1104+1333insGTGT		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 1558 AN: 54170 Hom.: 110 Cov.: 18

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0277

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0215

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0152

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00832 AC: 1778 AN: 213682 AF XY: 0.00809

Gnomad AFR exome AF: 0.00556

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00555

Gnomad EAS exome AF: 0.0193

Gnomad FIN exome AF: 0.00298

Gnomad NFE exome AF: 0.00875

Gnomad OTH exome AF: 0.00824

GnomAD4 exome AF: 0.0229 AC: 8773 AN: 382636 Hom.: 451 Cov.: 0 AF XY: 0.0222 AC XY: 4817 AN XY: 216548

African (AFR) AF: 0.0124 AC: 136 AN: 11002

American (AMR) AF: 0.0128 AC: 450 AN: 35254

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 151 AN: 12666

East Asian (EAS) AF: 0.0386 AC: 680 AN: 17594

South Asian (SAS) AF: 0.00569 AC: 333 AN: 58572

European-Finnish (FIN) AF: 0.0178 AC: 457 AN: 25730

Middle Eastern (MID) AF: 0.00784 AC: 16 AN: 2042

European-Non Finnish (NFE) AF: 0.0300 AC: 6053 AN: 201744

Other (OTH) AF: 0.0276 AC: 497 AN: 18032

GnomAD4 genome AF: 0.0288 AC: 1561 AN: 54198 Hom.: 110 Cov.: 18 AF XY: 0.0279 AC XY: 667 AN XY: 23890

African (AFR) AF: 0.0172 AC: 237 AN: 13776

American (AMR) AF: 0.0235 AC: 71 AN: 3018

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 39 AN: 1812

East Asian (EAS) AF: 0.0377 AC: 67 AN: 1776

South Asian (SAS) AF: 0.00749 AC: 11 AN: 1468

European-Finnish (FIN) AF: 0.00612 AC: 4 AN: 654

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

European-Non Finnish (NFE) AF: 0.0363 AC: 1105 AN: 30454

Other (OTH) AF: 0.0174 AC: 11 AN: 632

Alfa AF: 0.0140 Hom.: 31

ClinVar

Not reported in ClinVar

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;