6-55759124-T-TACACACACAC

Position:

• chr6-55759124-T-TACACACACAC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_021073.4(BMP5):​c.1105-10_1105-9insGTGTGTGTGT 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., cov: 18)
  • Exomes 𝑓: 0.013 (389 hom.)
• Consequence: BMP5 NM_021073.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign no assertion criteria provided 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 -9 ACMG points.

• BP6: Variant 6-55759124-T-TACACACACAC is Benign according to our data. Variant chr6-55759124-T-TACACACACAC is described in ClinVar as [Likely_benign]. Clinvar id is 3037354.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0156 (848/54206) while in subpopulation NFE AF= 0.0229 (696/30458). AF 95% confidence interval is 0.0214. There are 32 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 18. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 848 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP5	NM_021073.4	c.1105-10_1105-9insGTGTGTGTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370830.4	NP_066551.1
BMP5	NM_001329754.2	c.1104+1332_1104+1333insGTGTGTGTGT		intron_variant			NP_001316683.1
BMP5	NM_001329756.2	c.1028-3443_1028-3442insGTGTGTGTGT		intron_variant			NP_001316685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.1105-10_1105-9insGTGTGTGTGT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021073.4	ENSP00000359866	P1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 847 AN: 54176 Hom.: 32 Cov.: 18

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.0369

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0171

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00136

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0152

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.00799

GnomAD3 exomes AF: 0.00263 AC: 562 AN: 213682 Hom.: 50 AF XY: 0.00256 AC XY: 298 AN XY: 116414

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000587

Gnomad FIN exome AF: 0.000851

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00402

GnomAD4 exome AF: 0.0132 AC: 5064 AN: 382918 Hom.: 389 Cov.: 0 AF XY: 0.0125 AC XY: 2715 AN XY: 216710

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.00995

Gnomad4 EAS exome AF: 0.0000567

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0156 AC: 848 AN: 54206 Hom.: 32 Cov.: 18 AF XY: 0.0145 AC XY: 347 AN XY: 23890

Gnomad4 AFR AF: 0.00297

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0171

Gnomad4 EAS AF: 0.000563

Gnomad4 SAS AF: 0.00136

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.00791

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BMP5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

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;