6-55759124-T-TAC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_021073.4(BMP5):c.1105-10_1105-9insGT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 18)
  • Exomes 𝑓: 0.024 (202 hom.)
• Consequence: BMP5 NM_021073.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Benign. Variant got -10 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 id is 3060530.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 18. This position pass quality control queck.
• BS2: High AC in GnomAd at 1343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP5	NM_021073.4	c.1105-10_1105-9insGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370830.4
BMP5	NM_001329754.2	c.1104+1332_1104+1333insGT		intron_variant
BMP5	NM_001329756.2	c.1028-3443_1028-3442insGT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP5	ENST00000370830.4	c.1105-10_1105-9insGT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021073.4	P1

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

GnomAD3 exomes AF: 0.0113 AC: 2407 AN: 213682 Hom.: 87 AF XY: 0.0117 AC XY: 1366 AN XY: 116414

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 SAS exome AF: 0.0153

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

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00968

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0283

Gnomad4 OTH exome AF: 0.0273

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

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0293

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.0136

Gnomad4 FIN AF: 0.00917

Gnomad4 NFE AF: 0.0265

Gnomad4 OTH AF: 0.0285

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BMP5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749127959; hg19: chr6-55623922;