6-7727038-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001718.6(BMP6):c.83G>A(p.Arg28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,134,860 control chromosomes in the GnomAD database, including 117,458 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10975 hom., cov: 33)
  • Exomes 𝑓: 0.46 (106483 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0780

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.26759205E-5).
• BP6: Variant 6-7727038-G-A is Benign according to our data. Variant chr6-7727038-G-A is described in ClinVar as [Benign]. Clinvar id is 3058879.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7727038-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP6	NM_001718.6	c.83G>A	p.Arg28Gln	missense_variant	1/7	ENST00000283147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP6	ENST00000283147.7	c.83G>A	p.Arg28Gln	missense_variant	1/7	1	NM_001718.6	P1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 54797 AN: 148784 Hom.: 10973 Cov.: 33

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.359

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.598 AC: 360 AN: 602 Hom.: 105 AF XY: 0.621 AC XY: 174 AN XY: 280

Gnomad AFR exome AF: 0.500

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.462 AC: 455249 AN: 985968 Hom.: 106483 Cov.: 30 AF XY: 0.462 AC XY: 214761 AN XY: 464384

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.471

Gnomad4 OTH exome AF: 0.442

GnomAD4 genome AF: 0.368 AC: 54819 AN: 148892 Hom.: 10975 Cov.: 33 AF XY: 0.365 AC XY: 26512 AN XY: 72606

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.528

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.347

Alfa AF: 0.276 Hom.: 712

Bravo AF: 0.347

TwinsUK AF: 0.462 AC: 1713

ALSPAC AF: 0.464 AC: 1787

ExAC AF: 0.238 AC: 166

Asia WGS AF: 0.343 AC: 1056 AN: 3080

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BMP6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.061
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.021	B
Vest4		0.096
MPC		0.18
ClinPred		0.017	T
GERP RS		-1.7
Varity_R		0.027
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs111588693; hg19: chr6-7727271; COSMIC: COSV51660630;