NM_001718.6:c.287T>C

Variant names:

• chr6-7727242-T-C
• rs200573175
• NM_001718.6:c.287T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (39 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 1.51
• Publications: 11 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: Benign. The variant received -10 ACMG points.

• 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 VariationId is 1801215.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 622 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.287T>C	p.Leu96Pro	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.287T>C	p.Leu96Pro	missense	Exon 1 of 7	ENSP00000283147.6	P22004
	BMP6	ENST00000946083.1		c.287T>C	p.Leu96Pro	missense	Exon 1 of 7	ENSP00000616142.1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152122 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00339 AC: 756 AN: 223016 AF XY: 0.00356

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 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.: 39 Cov.: 32 AF XY: 0.00602 AC XY: 4351 AN XY: 723064

African (AFR) AF: 0.000990 AC: 33 AN: 33348

American (AMR) AF: 0.00231 AC: 102 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00197 AC: 51 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85726

European-Finnish (FIN) AF: 0.00264 AC: 134 AN: 50808

Middle Eastern (MID) AF: 0.00298 AC: 17 AN: 5706

European-Non Finnish (NFE) AF: 0.00748 AC: 8297 AN: 1109224

Other (OTH) AF: 0.00472 AC: 283 AN: 59948

GnomAD4 genome AF: 0.00409 AC: 622 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74444

African (AFR) AF: 0.00130 AC: 54 AN: 41562

American (AMR) AF: 0.00647 AC: 99 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10606

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00632 AC: 430 AN: 67988

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00569 Hom.: 0

Bravo AF: 0.00442

ESP6500AA AF: 0.000743 AC: 3

ESP6500EA AF: 0.00213 AC: 17

ExAC AF: 0.00309 AC: 363

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	BMP6-related disorder (1)
-	-	1	not provided (1)
-	-	-	Iron overload, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.29
Sift	Benign	0.097	T
Sift4G	Benign	0.20	T
Polyphen		0.77	P
Vest4		0.80
MVP		0.75
MPC		0.78
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.29
gMVP		0.41
Mutation Taster		=69/31	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: rs200573175; hg19: chr6-7727475; COSMIC: COSV51671163;