20-6770235-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001200.4(BMP2):c.109T>G(p.Ser37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,603,848 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (45 hom., cov: 32)
  • Exomes 𝑓: 0.021 (507 hom.)
• Consequence: BMP2 NM_001200.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001722455).
• BP6: Variant 20-6770235-T-G is Benign according to our data. Variant chr20-6770235-T-G is described in ClinVar as [Benign]. Clinvar id is 195137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-6770235-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2	NM_001200.4	c.109T>G	p.Ser37Ala	missense_variant	2/3	ENST00000378827.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2	ENST00000378827.5	c.109T>G	p.Ser37Ala	missense_variant	2/3	1	NM_001200.4	P1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2468 AN: 152088 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0178

GnomAD3 exomes AF: 0.0236 AC: 5335 AN: 226254 Hom.: 131 AF XY: 0.0247 AC XY: 3055 AN XY: 123662

Gnomad AFR exome AF: 0.00237

Gnomad AMR exome AF: 0.00710

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.0923

Gnomad SAS exome AF: 0.0442

Gnomad FIN exome AF: 0.00977

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0211 AC: 30610 AN: 1451642 Hom.: 507 Cov.: 31 AF XY: 0.0217 AC XY: 15629 AN XY: 721436

Gnomad4 AFR exome AF: 0.00226

Gnomad4 AMR exome AF: 0.00765

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0953

Gnomad4 SAS exome AF: 0.0429

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0162 AC: 2470 AN: 152206 Hom.: 45 Cov.: 32 AF XY: 0.0168 AC XY: 1247 AN XY: 74402

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0843

Gnomad4 SAS AF: 0.0499

Gnomad4 FIN AF: 0.00942

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0195

Alfa AF: 0.0198 Hom.: 47

Bravo AF: 0.0150

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0214 AC: 2583

Asia WGS AF: 0.0640 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 14691541, 23506588) -

Ventricular septal defect 1 Benign:1

Benign, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	2.8
Dann	Benign	0.35
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.086
Sift	Benign	0.91	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.35
ClinPred		0.0023	T
GERP RS		-10
Varity_R		0.030
gMVP		0.28

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: rs2273073; hg19: chr20-6750882; COSMIC: COSV66576910;