6-55759124-TACACACACACAC-TACACACACACACAC

Variant names:

• chr6-55759124-T-TAC
• rs749127959
• NM_021073.4:c.1105-11_1105-10dupGT

Variant summary

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

The NM_021073.4(BMP5):​c.1105-11_1105-10dupGT 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 0.025 (66 hom., cov: 18)
  • Exomes 𝑓: 0.024 (202 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-TAC is Benign according to our data. Variant chr6-55759124-T-TAC is described in ClinVar as Likely_benign. ClinVar VariationId is 3060530.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0248 (1344/54212) while in subpopulation NFE AF = 0.0265 (809/30472). AF 95% confidence interval is 0.025. There are 66 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 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.1105-11_1105-10dupGT		intron	N/A	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1331_1104+1332dupGT		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3444_1028-3443dupGT		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_1105-9insGT		intron	N/A	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1332_1104+1333insGT		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 1343 AN: 54182 Hom.: 66 Cov.: 18

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.0129

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0293

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00917

Gnomad MID AF: 0.0606

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0288

GnomAD2 exomes AF: 0.0113 AC: 2407 AN: 213682 AF XY: 0.0117

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00927

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00887

Gnomad FIN exome AF: 0.00681

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0240 AC: 9172 AN: 381964 Hom.: 202 Cov.: 0 AF XY: 0.0244 AC XY: 5275 AN XY: 216182

African (AFR) AF: 0.0246 AC: 271 AN: 10994

American (AMR) AF: 0.00968 AC: 341 AN: 35232

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 320 AN: 12640

East Asian (EAS) AF: 0.0184 AC: 324 AN: 17562

South Asian (SAS) AF: 0.0197 AC: 1155 AN: 58506

European-Finnish (FIN) AF: 0.0200 AC: 513 AN: 25672

Middle Eastern (MID) AF: 0.0285 AC: 58 AN: 2036

European-Non Finnish (NFE) AF: 0.0283 AC: 5699 AN: 201326

Other (OTH) AF: 0.0273 AC: 491 AN: 17996

GnomAD4 genome AF: 0.0248 AC: 1344 AN: 54212 Hom.: 66 Cov.: 18 AF XY: 0.0249 AC XY: 595 AN XY: 23888

African (AFR) AF: 0.0258 AC: 356 AN: 13774

American (AMR) AF: 0.0156 AC: 47 AN: 3018

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 53 AN: 1810

East Asian (EAS) AF: 0.0135 AC: 24 AN: 1776

South Asian (SAS) AF: 0.0136 AC: 20 AN: 1468

European-Finnish (FIN) AF: 0.00917 AC: 6 AN: 654

Middle Eastern (MID) AF: 0.0606 AC: 4 AN: 66

European-Non Finnish (NFE) AF: 0.0265 AC: 809 AN: 30472

Other (OTH) AF: 0.0285 AC: 18 AN: 632

Alfa AF: 0.0143 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;