chr6-7727238-C-T

Position:

• chr6-7727238-C-T

Variant summary

Our verdict is Likely benign. Variant got -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 same amino acid change has been previously reported as Likely pathogenicin 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

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
BMP6	NM_001718.6	c.283C>T	p.Pro95Ser	missense_variant	1/7	ENST00000283147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP6	ENST00000283147.7	c.283C>T	p.Pro95Ser	missense_variant	1/7	1	NM_001718.6	P1

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

GnomAD3 exomes AF: 0.000242 AC: 54 AN: 223056 Hom.: 1 AF XY: 0.000275 AC XY: 34 AN XY: 123772

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 SAS exome AF: 0.000909

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

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000665

Gnomad4 FIN exome AF: 0.0000591

Gnomad4 NFE exome AF: 0.000363

Gnomad4 OTH exome AF: 0.000200

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

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

BMP6: BS2 -

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	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
MutationTaster	Benign	1.0	D
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

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;