chr6-55759124-T-TACACAC

Position:

• chr6-55759124-T-TACACAC

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_1105-9insGTGTGT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 18)
  • Exomes 𝑓: 0.0037 (70 hom.)
• Consequence: BMP5 NM_021073.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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-TACACAC is Benign according to our data. Variant chr6-55759124-T-TACACAC is described in ClinVar as [Benign]. Clinvar id is 735236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0038 (206/54232) while in subpopulation EAS AF= 0.027 (48/1776). AF 95% confidence interval is 0.0209. There are 4 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 18. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 205 AN: 54202 Hom.: 4 Cov.: 18

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00369

Gnomad AMR AF: 0.00398

Gnomad ASJ AF: 0.000552

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00181 AC: 387 AN: 213682 Hom.: 31 AF XY: 0.00163 AC XY: 190 AN XY: 116414

Gnomad AFR exome AF: 0.000422

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.000555

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.00172

Gnomad FIN exome AF: 0.0000709

Gnomad NFE exome AF: 0.000665

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00367 AC: 1405 AN: 382928 Hom.: 70 Cov.: 0 AF XY: 0.00365 AC XY: 792 AN XY: 216714

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0236

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00380 AC: 206 AN: 54232 Hom.: 4 Cov.: 18 AF XY: 0.00343 AC XY: 82 AN XY: 23898

Gnomad4 AFR AF: 0.00232

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.000552

Gnomad4 EAS AF: 0.0270

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00153

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00633

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2018

- -

BMP5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 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;