rs756121523

Variant names:

• chr6-7727124-C-T
• rs756121523
• NM_001718.6:c.169C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001718.6(BMP6):​c.169C>T​(p.Pro57Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000874 in 1,373,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.10737407).
• BS2: High AC in GnomAdExome4 at 12 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.169C>T	p.Pro57Ser	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.169C>T	p.Pro57Ser	missense	Exon 1 of 7	ENSP00000283147.6	P22004
	BMP6	ENST00000946083.1		c.169C>T	p.Pro57Ser	missense	Exon 1 of 7	ENSP00000616142.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000253 AC: 3 AN: 118720 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000473

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000231

Gnomad OTH exome AF: 0.000305

GnomAD4 exome AF: 0.00000874 AC: 12 AN: 1373616 Hom.: 0 Cov.: 32 AF XY: 0.00000737 AC XY: 5 AN XY: 678156

African (AFR) AF: 0.00 AC: 0 AN: 28174

American (AMR) AF: 0.0000302 AC: 1 AN: 33084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24034

East Asian (EAS) AF: 0.00 AC: 0 AN: 31262

South Asian (SAS) AF: 0.00 AC: 0 AN: 77234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4952

European-Non Finnish (NFE) AF: 0.00000841 AC: 9 AN: 1070628

Other (OTH) AF: 0.0000351 AC: 2 AN: 56998

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000925 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.10
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.086
Sift	Benign	0.098	T
Sift4G	Benign	0.27	T
Polyphen		0.0020	B
Vest4		0.21
MutPred		0.22		Gain of phosphorylation at P57 (P = 0.0039)
MVP		0.55
MPC		0.60
ClinPred		0.18	T
GERP RS		0.48
Varity_R		0.026
gMVP		0.42
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs756121523; hg19: chr6-7727357; COSMIC: COSV51666044;