dbSNP rs201486498: BMP6:p.Glu112Lys (chr6-7727289-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001718.6(BMP6):c.334G>A(p.Glu112Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,453,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E112Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

BMP6
NM_001718.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.465

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hemochromatosis type 5
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
iron overload, susceptibility to
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BMP6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10159078).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001718.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP6	NM_001718.6	MANE Select	c.334G>A	p.Glu112Lys	missense	Exon 1 of 7	NP_001709.1	P22004

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP6	ENST00000283147.7	TSL:1 MANE Select	c.334G>A	p.Glu112Lys	missense	Exon 1 of 7	ENSP00000283147.6	P22004
	BMP6	ENST00000946083.1		c.334G>A	p.Glu112Lys	missense	Exon 1 of 7	ENSP00000616142.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000757

AC:

AN:

1453744

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.00

AC:

AN:

44148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39276

South Asian (SAS)

AF:

0.00

AC:

AN:

85578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1109262

Other (OTH)

AF:

0.0000334

AC:

AN:

59910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.6

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.22

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.44

M_CAP

Benign

0.0058

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.47

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.0

REVEL

Benign

0.088

Sift

Benign

0.89

Sift4G

Benign

0.37

Polyphen

0.056

Vest4

0.15

MutPred

0.43

Gain of ubiquitination at E112 (P = 0.0051)

MVP

0.68

MPC

0.18

ClinPred

0.043

GERP RS

-1.3

Varity_R

0.11

gMVP

0.39

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over