6-7727292-C-G

Variant names:

• chr6-7727292-C-G
• rs7745236
• NM_001718.6:c.337C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001718.6(BMP6):​c.337C>G​(p.Gln113Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,576,856 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q113Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (26 hom.)
• Consequence: BMP6 NM_001718.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 1.15
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046218634).
• BP6: Variant 6-7727292-C-G is Benign according to our data. Variant chr6-7727292-C-G is described in ClinVar as Benign. ClinVar VariationId is 1801216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00987 (1502/152102) while in subpopulation AFR AF = 0.0303 (1257/41532). AF 95% confidence interval is 0.0289. There are 17 homozygotes in GnomAd4. There are 693 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1502 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.337C>G	p.Gln113Glu	missense	Exon 1 of 7	NP_001709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP6	ENST00000283147.7	TSL:1 MANE Select	c.337C>G	p.Gln113Glu	missense	Exon 1 of 7	ENSP00000283147.6
	BMP6	ENST00000946083.1		c.337C>G	p.Gln113Glu	missense	Exon 1 of 7	ENSP00000616142.1

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1493 AN: 151990 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00409 AC: 832 AN: 203190 AF XY: 0.00353

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.00465

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.000194

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00197 AC: 2807 AN: 1424754 Hom.: 26 Cov.: 32 AF XY: 0.00179 AC XY: 1267 AN XY: 707140

African (AFR) AF: 0.0302 AC: 969 AN: 32102

American (AMR) AF: 0.00503 AC: 210 AN: 41780

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 309 AN: 25398

East Asian (EAS) AF: 0.000133 AC: 5 AN: 37518

South Asian (SAS) AF: 0.000181 AC: 15 AN: 82858

European-Finnish (FIN) AF: 0.0000419 AC: 2 AN: 47770

Middle Eastern (MID) AF: 0.0144 AC: 81 AN: 5610

European-Non Finnish (NFE) AF: 0.000859 AC: 939 AN: 1093138

Other (OTH) AF: 0.00473 AC: 277 AN: 58580

GnomAD4 genome AF: 0.00987 AC: 1502 AN: 152102 Hom.: 17 Cov.: 32 AF XY: 0.00932 AC XY: 693 AN XY: 74362

African (AFR) AF: 0.0303 AC: 1257 AN: 41532

American (AMR) AF: 0.00674 AC: 103 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10566

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 67956

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.00411 Hom.: 1

Bravo AF: 0.0115

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0160 AC: 63

ESP6500EA AF: 0.00191 AC: 15

ExAC AF: 0.00360 AC: 415

ClinVar

ClinVar submissions as Germline

Significance: 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	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.2
DANN	Benign	0.56
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.036
Sift	Benign	0.39	T
Sift4G	Benign	0.17	T
Polyphen		0.018	B
Vest4		0.29
MVP		0.49
MPC		0.17
ClinPred		0.0031	T
GERP RS		0.70
Varity_R		0.19
gMVP		0.27
Mutation Taster		=88/12	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: rs7745236; hg19: chr6-7727525;