rs200573175

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PS1_ModeratePM1BP4_StrongBP6_ModerateBS2

The NM_001718.6(BMP6):c.287T>C(p.Leu96Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,606,568 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.0041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 39 hom. )

Consequence

BMP6
NM_001718.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 1.51

Variant links:

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]

BMP6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PS1

Transcript NM_001718.6 (BMP6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a region_of_interest Disordered (size 42) in uniprot entity BMP6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001718.6

BP4

Computational evidence support a benign effect (MetaRNN=0.01876542).

BP6

Variant 6-7727242-T-C is Benign according to our data. Variant chr6-7727242-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1801215.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6 link	c.287T>C	p.Leu96Pro	missense_variant	Exon 1 of 7	ENST00000283147.7	NP_001709.1	P22004Q4VBA3B4DUF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP6	ENST00000283147.7 link	c.287T>C	p.Leu96Pro	missense_variant	Exon 1 of 7	1	NM_001718.6	ENSP00000283147.6		P22004

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

623

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00632

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00339

AC:

756

AN:

223016

Hom.:

AF XY:

0.00356

AC XY:

441

AN XY:

123802

show subpopulations

Gnomad AFR exome

AF:

0.000890

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.00225

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00619

Gnomad OTH exome

AF:

0.00436

GnomAD4 exome

AF:

0.00614

AC:

8929

AN:

1454330

Hom.:

Cov.:

AF XY:

0.00602

AC XY:

4351

AN XY:

723064

show subpopulations

Gnomad4 AFR exome

AF:

0.000990

Gnomad4 AMR exome

AF:

0.00231

Gnomad4 ASJ exome

AF:

0.00197

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00264

Gnomad4 NFE exome

AF:

0.00748

Gnomad4 OTH exome

AF:

0.00472

GnomAD4 genome

AF:

0.00409

AC:

622

AN:

152238

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00632

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00569

Hom.:

Bravo

AF:

0.00442

ESP6500AA

AF:

0.000743

AC:

ESP6500EA

AF:

0.00213

AC:

ExAC

AF:

0.00309

AC:

363

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMP6: BS2 -

BMP6-related disorder

Benign:1

May 30, 2024

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). -

Iron overload, susceptibility to

Other:1

Nov 28, 2022

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

-0.019

Eigen_PC

Benign

-0.047

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.76

REVEL

Benign

0.29

Sift

Benign

0.097

Sift4G

Benign

0.20

Polyphen

0.77

Vest4

0.80

MVP

0.75

MPC

0.78

ClinPred

0.017

GERP RS

3.3

Varity_R

0.29

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over