rs34183594

chr20-6778380-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001200.4(BMP2):c.482T>C(p.Leu161Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: BMP2 NM_001200.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

BMP2 (HGNC:1069): (bone morphogenetic protein 2) 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, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053322017).
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2	NM_001200.4	c.482T>C	p.Leu161Ser	missense_variant	3/3	ENST00000378827.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2	ENST00000378827.5	c.482T>C	p.Leu161Ser	missense_variant	3/3	1	NM_001200.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251320 Hom.: 1 AF XY: 0.0000809 AC XY: 11 AN XY: 135896

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the BMP2 protein (p.Leu161Ser). This variant is present in population databases (rs34183594, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with BMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1038630). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Benign	0.70
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.030	N
MutationTaster	Benign	0.86	D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.16
Sift	Benign	0.46	T
Sift4G	Benign	0.79	T
Polyphen		0.78	P
Vest4		0.079
MVP		0.73
MPC		1.5
ClinPred		0.11	T
GERP RS		4.7
Varity_R		0.045
gMVP		0.30

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: rs34183594; hg19: chr20-6759027;