NM_001718.6:c.337C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 4P and 14B. PS1_ModeratePM1BP4_StrongBP6_ModerateBS1BS2

The NM_001718.6(BMP6):c.337C>G(p.Gln113Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,576,856 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.0099 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 26 hom. )

Consequence

BMP6
NM_001718.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 1.15

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 Benign. Variant got -10 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=0.0046218634).

BP6

Variant 6-7727292-C-G is Benign according to our data. Variant chr6-7727292-C-G is described in ClinVar as [Benign]. Clinvar id is 1801216.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00987 (1502/152102) while in subpopulation AFR AF= 0.0303 (1257/41532). AF 95% confidence interval is 0.0289. There are 17 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6 link	c.337C>G	p.Gln113Glu	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.337C>G	p.Gln113Glu	missense_variant	Exon 1 of 7	1	NM_001718.6	ENSP00000283147.6		P22004

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

1493

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.00409

AC:

832

AN:

203190

Hom.:

AF XY:

0.00353

AC XY:

398

AN XY:

112636

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.00465

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.000194

Gnomad SAS exome

AF:

0.000181

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00687

GnomAD4 exome

AF:

0.00197

AC:

2807

AN:

1424754

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1267

AN XY:

707140

show subpopulations

Gnomad4 AFR exome

AF:

0.0302

Gnomad4 AMR exome

AF:

0.00503

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.000133

Gnomad4 SAS exome

AF:

0.000181

Gnomad4 FIN exome

AF:

0.0000419

Gnomad4 NFE exome

AF:

0.000859

Gnomad4 OTH exome

AF:

0.00473

GnomAD4 genome

AF:

0.00987

AC:

1502

AN:

152102

Hom.:

Cov.:

AF XY:

0.00932

AC XY:

693

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0160

AC:

ESP6500EA

AF:

0.00191

AC:

ExAC

AF:

0.00360

AC:

415

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMP6: BS1, BS2 -

BMP6-related disorder

Benign:1

Feb 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

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

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.2

DANN

Benign

0.56

DEOGEN2

Benign

0.22

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.040

REVEL

Benign

0.036

Sift

Benign

0.39

Sift4G

Benign

0.17

Polyphen

0.018

Vest4

0.29

MVP

0.49

MPC

0.17

ClinPred

0.0031

GERP RS

0.70

Varity_R

0.19

gMVP

0.27

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