6-7727220-C-T

Variant names:

• chr6-7727220-C-T
• rs758074194
• NM_001718.6:c.265C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001718.6(BMP6):​c.265C>T​(p.Leu89Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,453,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.965

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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP6	NM_001718.6	c.265C>T	p.Leu89Phe	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.265C>T	p.Leu89Phe	missense_variant	Exon 1 of 7	1	NM_001718.6	ENSP00000283147.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 222104 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453330 Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11 AN XY: 722520

Gnomad4 AFR exome AF: 0.0000300 AC: 1 AN: 33296

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44006

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25892

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39364

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85634

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50724

Gnomad4 NFE exome AF: 0.0000144 AC: 16 AN: 1108794

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59910

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000846 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265C>T (p.L89F) alteration is located in exon 1 (coding exon 1) of the BMP6 gene. This alteration results from a C to T substitution at nucleotide position 265, causing the leucine (L) at amino acid position 89 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.0041	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.69		Loss of glycosylation at P93 (P = 0.1249);
MVP		0.80
MPC		0.71
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.61
gMVP		0.62
Mutation Taster		=66/34	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

Publications

LitVar

Other links and lift over

dbSNP: rs758074194; hg19: chr6-7727453;