6-55759124-TAC-T

Position:

• chr6-55759124-TAC-T

Variant summary

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

The ENST00000370830.4(BMP5):​c.1105-11_1105-10del variant causes a splice polypyrimidine tract, 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 ENST00000370830.4 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-TAC-T is Benign according to our data. Variant chr6-55759124-TAC-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038228.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0169 (6401/377850) while in subpopulation EAS AF= 0.0325 (562/17314). AF 95% confidence interval is 0.0302. There are 5 homozygotes in gnomad4_exome. There are 3615 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP5	NM_021073.4	c.1105-11_1105-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370830.4	NP_066551.1
BMP5	NM_001329754.2	c.1104+1331_1104+1332del		intron_variant			NP_001316683.1
BMP5	NM_001329756.2	c.1028-3444_1028-3443del		intron_variant			NP_001316685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.1105-11_1105-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021073.4	ENSP00000359866	P1

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

GnomAD3 exomes AF: 0.00694 AC: 1484 AN: 213682 Hom.: 8 AF XY: 0.00732 AC XY: 852 AN XY: 116414

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 SAS exome AF: 0.0130

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

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.00907

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.0325

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0206

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

Gnomad4 AFR AF: 0.000580

Gnomad4 AMR AF: 0.00331

Gnomad4 ASJ AF: 0.00221

Gnomad4 EAS AF: 0.00225

Gnomad4 SAS AF: 0.00136

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00

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 22, 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs749127959; hg19: chr6-55623922;