6-55759124-TACACACACACAC-TACACAC

Variant names:

• chr6-55759124-TACACAC-T
• rs749127959
• NM_021073.4:c.1105-15_1105-10delGTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021073.4(BMP5):​c.1105-15_1105-10delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000522 in 383,018 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000052 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1105-15_1105-10delGTGTGT		intron	N/A	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1327_1104+1332delGTGTGT		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3448_1028-3443delGTGTGT		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.1105-15_1105-10delGTGTGT		intron	N/A	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1327_1104+1332delGTGTGT		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome AF: 0.00000522 AC: 2 AN: 383018 Hom.: 0 AF XY: 0.00000923 AC XY: 2 AN XY: 216762

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

African (AFR) AF: 0.00 AC: 0 AN: 11012

American (AMR) AF: 0.00 AC: 0 AN: 35272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12672

East Asian (EAS) AF: 0.00 AC: 0 AN: 17624

South Asian (SAS) AF: 0.0000171 AC: 1 AN: 58592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2042

European-Non Finnish (NFE) AF: 0.00000495 AC: 1 AN: 202008

Other (OTH) AF: 0.00 AC: 0 AN: 18056

⚠️ 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 Cov.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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;