6-7727242-T-C

Position:

• chr6-7727242-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PS1_Moderate PM1 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. 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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

• 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

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]

ACMG classification

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/exons	MANE	Protein	UniProt
BMP6	NM_001718.6	c.287T>C	p.Leu96Pro	missense_variant	1/7	ENST00000283147.7	NP_001709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP6	ENST00000283147.7	c.287T>C	p.Leu96Pro	missense_variant	1/7	1	NM_001718.6	ENSP00000283147	P1

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

GnomAD3 exomes AF: 0.00339 AC: 756 AN: 223016 Hom.: 0 AF XY: 0.00356 AC XY: 441 AN XY: 123802

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

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.: 0 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74444

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.: 0

Bravo AF: 0.00442

ESP6500AA AF: 0.000743 AC: 3

ESP6500EA AF: 0.00213 AC: 17

ExAC AF: 0.00309 AC: 363

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

BMP6: BS2 -

BMP6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

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

risk factor, no assertion criteria provided

literature only

OMIM

Nov 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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

Other links and lift over

dbSNP: rs200573175; hg19: chr6-7727475; COSMIC: COSV51671163;