4-81046456-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001201.5(BMP3):c.1035G>C(p.Lys345Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,614,052 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (32 hom.)
• Consequence: BMP3 NM_001201.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

Genes affected

BMP3 (HGNC:1070): (bone morphogenetic protein 3) 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 suppresses osteoblast differentiation, and negatively regulates bone density, by modulating TGF-beta receptor availability to other ligands. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008763164).
• BP6: Variant 4-81046456-G-C is Benign according to our data. Variant chr4-81046456-G-C is described in ClinVar as [Benign]. Clinvar id is 774615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-81046456-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1526/152302) while in subpopulation AFR AF= 0.0284 (1182/41556). AF 95% confidence interval is 0.0271. There are 18 homozygotes in gnomad4. There are 746 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP3	NM_001201.5	c.1035G>C	p.Lys345Asn	missense_variant	2/3	ENST00000282701.4
BMP3	XM_006714291.4	c.1035G>C	p.Lys345Asn	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP3	ENST00000282701.4	c.1035G>C	p.Lys345Asn	missense_variant	2/3	1	NM_001201.5	P1

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1512 AN: 152184 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00424 AC: 1064 AN: 250836 Hom.: 13 AF XY: 0.00370 AC XY: 501 AN XY: 135546

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00336

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00366 AC: 5355 AN: 1461750 Hom.: 32 Cov.: 34 AF XY: 0.00357 AC XY: 2599 AN XY: 727166

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00357

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.0100 AC: 1526 AN: 152302 Hom.: 18 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74470

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00300 Hom.: 1

Bravo AF: 0.0110

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00491 AC: 596

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00295

EpiControl AF: 0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Benign	0.060	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.31		Loss of glycosylation at P342 (P = 0.0031);
MVP		0.81
MPC		0.24
ClinPred		0.061	T
GERP RS		1.0
Varity_R		0.15
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61729826; hg19: chr4-81967610; COSMIC: COSV51083377;