6-7727292-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_Moderate BP4_Strong BP6_Very_Strong 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. 14/20 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. 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/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.15

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 Benign. Variant got -18 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=0.0046218634).
• BP6: Variant 6-7727292-C-G is Benign according to our data. Variant chr6-7727292-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1801216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP6	NM_001718.6	c.337C>G	p.Gln113Glu	missense_variant	1/7	ENST00000283147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP6	ENST00000283147.7	c.337C>G	p.Gln113Glu	missense_variant	1/7	1	NM_001718.6	P1

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

GnomAD3 exomes AF: 0.00409 AC: 832 AN: 203190 Hom.: 7 AF XY: 0.00353 AC XY: 398 AN XY: 112636

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 SAS exome AF: 0.000181

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

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.000133

Gnomad4 SAS exome AF: 0.000181

Gnomad4 FIN exome AF: 0.0000419

Gnomad4 NFE exome AF: 0.000859

Gnomad4 OTH exome AF: 0.00473

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

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.0142

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

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

BMP6: BS1, BS2 -

BMP6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely 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	0.069
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
MutationTaster	Benign	1.0	N
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

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: rs7745236; hg19: chr6-7727525;