6-7727238-C-T

Variant names:

• chr6-7727238-C-T
• rs199518216
• NM_001718.6:c.283C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PS1_Moderate BP4 BP6_Moderate

The NM_001718.6(BMP6):​c.283C>T​(p.Pro95Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000327 in 1,606,518 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P95L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 5.34

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PS1: Transcript NM_001718.6 (BMP6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.40516105).
• BP6: Variant 6-7727238-C-T is Benign according to our data. Variant chr6-7727238-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1801214.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 7	ENST00000283147.7	NP_001709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP6	ENST00000283147.7	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 7	1	NM_001718.6	ENSP00000283147.6

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000242 AC: 54 AN: 223056 AF XY: 0.000275

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000155

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.000343 AC: 499 AN: 1454206 Hom.: 1 Cov.: 32 AF XY: 0.000353 AC XY: 255 AN XY: 723016

Gnomad4 AFR exome AF: 0.0000900 AC: 3 AN: 33322

Gnomad4 AMR exome AF: 0.000362 AC: 16 AN: 44142

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25924

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39462

Gnomad4 SAS exome AF: 0.000665 AC: 57 AN: 85710

Gnomad4 FIN exome AF: 0.0000591 AC: 3 AN: 50780

Gnomad4 NFE exome AF: 0.000363 AC: 403 AN: 1109220

Gnomad4 Remaining exome AF: 0.000200 AC: 12 AN: 59938

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74482

Gnomad4 AFR AF: 0.0000481 AC: 0.0000480885 AN: 0.0000480885

Gnomad4 AMR AF: 0.000196 AC: 0.000196027 AN: 0.000196027

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000387 AC: 0.000386698 AN: 0.000386698

Gnomad4 SAS AF: 0.000414 AC: 0.000413907 AN: 0.000413907

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.00016175 AN: 0.00016175

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000871 AC: 7

ExAC AF: 0.000306 AC: 36

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMP6: BS2 -

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	Uncertain	0.47
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.37
Sift	Benign	0.054	T
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.73
MPC		0.57
ClinPred		0.26	T
GERP RS		1.5
Varity_R		0.21
gMVP		0.57
Mutation Taster		=50/50

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: rs199518216; hg19: chr6-7727471;