6-55759124-TACACACACACAC-TACACACACAC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_021073.4(BMP5):​c.1105-11_1105-10delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 432,076 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 13)
  • Exomes 𝑓: 0.017 (5 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 6-55759124-TAC-T is Benign according to our data. Variant chr6-55759124-TAC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3038228.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 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_1105-10delGT		intron	N/A	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1331_1104+1332delGT		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3444_1028-3443delGT		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.1105-11_1105-10delGT		intron	N/A	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1331_1104+1332delGT		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 72 AN: 54196 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00332

Gnomad ASJ AF: 0.00221

Gnomad EAS AF: 0.00225

Gnomad SAS AF: 0.00136

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00694 AC: 1484 AN: 213682 AF XY: 0.00732

Gnomad AFR exome AF: 0.00450

Gnomad AMR exome AF: 0.00638

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00715

Gnomad FIN exome AF: 0.00475

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.0169 AC: 6401 AN: 377850 Hom.: 5 AF XY: 0.0169 AC XY: 3615 AN XY: 213658

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

African (AFR) AF: 0.0127 AC: 139 AN: 10928

American (AMR) AF: 0.00907 AC: 318 AN: 35046

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 257 AN: 12386

East Asian (EAS) AF: 0.0325 AC: 562 AN: 17314

South Asian (SAS) AF: 0.0131 AC: 753 AN: 57622

European-Finnish (FIN) AF: 0.0148 AC: 376 AN: 25440

Middle Eastern (MID) AF: 0.0173 AC: 35 AN: 2026

European-Non Finnish (NFE) AF: 0.0180 AC: 3594 AN: 199290

Other (OTH) AF: 0.0206 AC: 367 AN: 17798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00133 AC: 72 AN: 54226 Hom.: 0 Cov.: 13 AF XY: 0.00109 AC XY: 26 AN XY: 23892

African (AFR) AF: 0.000580 AC: 8 AN: 13788

American (AMR) AF: 0.00331 AC: 10 AN: 3018

Ashkenazi Jewish (ASJ) AF: 0.00221 AC: 4 AN: 1812

East Asian (EAS) AF: 0.00225 AC: 4 AN: 1776

South Asian (SAS) AF: 0.00136 AC: 2 AN: 1468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.00144 AC: 44 AN: 30470

Other (OTH) AF: 0.00 AC: 0 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs749127959; hg19: chr6-55623922;