6-7727289-G-GAGC

Variant names:

• chr6-7727289-G-GAGC
• rs537332654
• NM_001718.6:c.353_355dupAGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001718.6(BMP6):​c.353_355dupAGC​(p.Gln118dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,605,868 control chromosomes in the GnomAD database, including 763 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (123 hom., cov: 32)
  • Exomes 𝑓: 0.019 (640 hom.)
• Consequence: BMP6 NM_001718.6 disruptive_inframe_insertion
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.869

Genes affected

BMP6 (HGNC:1073): (bone morphogenetic protein 6) 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. This protein regulates a wide range of biological processes including iron homeostasis, fat and bone development, and ovulation. Differential expression of this gene may be associated with progression of breast and prostate cancer. Mutations in this gene may be associated with iron overload in human patients. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-7727289-G-GAGC is Benign according to our data. Variant chr6-7727289-G-GAGC is described in ClinVar as [Benign]. Clinvar id is 3037636.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6	c.353_355dupAGC	p.Gln118dup	disruptive_inframe_insertion	Exon 1 of 7	ENST00000283147.7	NP_001709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP6	ENST00000283147.7	c.353_355dupAGC	p.Gln118dup	disruptive_inframe_insertion	Exon 1 of 7	1	NM_001718.6	ENSP00000283147.6

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4015 AN: 152048 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0593

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0365 AC: 7569 AN: 207432 AF XY: 0.0358

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0189 AC: 27480 AN: 1453704 Hom.: 640 Cov.: 32 AF XY: 0.0199 AC XY: 14392 AN XY: 722698

Gnomad4 AFR exome AF: 0.0307 AC: 1021 AN: 33224

Gnomad4 AMR exome AF: 0.0296 AC: 1307 AN: 44142

Gnomad4 ASJ exome AF: 0.0127 AC: 330 AN: 25946

Gnomad4 EAS exome AF: 0.148 AC: 5804 AN: 39258

Gnomad4 SAS exome AF: 0.0515 AC: 4407 AN: 85574

Gnomad4 FIN exome AF: 0.0410 AC: 2080 AN: 50682

Gnomad4 NFE exome AF: 0.00980 AC: 10867 AN: 1109254

Gnomad4 Remaining exome AF: 0.0257 AC: 1541 AN: 59908

GnomAD4 genome AF: 0.0264 AC: 4024 AN: 152164 Hom.: 123 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74378

Gnomad4 AFR AF: 0.0298 AC: 0.0297685 AN: 0.0297685

Gnomad4 AMR AF: 0.0212 AC: 0.0212391 AN: 0.0212391

Gnomad4 ASJ AF: 0.00980 AC: 0.00980392 AN: 0.00980392

Gnomad4 EAS AF: 0.164 AC: 0.16433 AN: 0.16433

Gnomad4 SAS AF: 0.0593 AC: 0.0593115 AN: 0.0593115

Gnomad4 FIN AF: 0.0485 AC: 0.0484785 AN: 0.0484785

Gnomad4 NFE AF: 0.0107 AC: 0.0106793 AN: 0.0106793

Gnomad4 OTH AF: 0.0246 AC: 0.0245979 AN: 0.0245979

Alfa AF: 0.00853 Hom.: 4

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BMP6-related disorder Benign:1

Dec 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=65/35	polymorphism (auto)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs537332654; hg19: chr6-7727522; COSMIC: COSV51662890;