rs17563

Variant names:

• chr14-53950804-A-G
• rs17563
• NM_001202.6:c.455T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-53950804-A-G
• chr14-53950804-A-C
• chr14-53950804-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001202.6(BMP4):​c.455T>C​(p.Val152Ala) variant causes a missense change. The variant allele was found at a frequency of 0.519 in 1,612,580 control chromosomes in the GnomAD database, including 227,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16493 hom., cov: 33)
  • Exomes 𝑓: 0.53 (210649 hom.)
• Consequence: BMP4 NM_001202.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.23
• Publications: 217 publications found

Genes affected

BMP4 (HGNC:1071): (bone morphogenetic protein 4) 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 heart development and adipogenesis. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. The encoded protein may also be involved in the pathology of multiple cardiovascular diseases and human cancers. [provided by RefSeq, Jul 2016]

BMP4 Gene-Disease associations (from GenCC):

• BMP4-related ocular growth disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• microphthalmia with brain and digit anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 11

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.141868E-4).
• BP6: Variant 14-53950804-A-G is Benign according to our data. Variant chr14-53950804-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001202.6. 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
	BMP4	NM_001202.6	MANE Select	c.455T>C	p.Val152Ala	missense	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.596T>C	p.Val199Ala	missense	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.455T>C	p.Val152Ala	missense	Exon 3 of 3	NP_001334843.1	P12644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	ENST00000245451.9	TSL:1 MANE Select	c.455T>C	p.Val152Ala	missense	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.455T>C	p.Val152Ala	missense	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.455T>C	p.Val152Ala	missense	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66805 AN: 152032 Hom.: 16484 Cov.: 33

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.453 AC: 112585 AN: 248720 AF XY: 0.459

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.527 AC: 769729 AN: 1460430 Hom.: 210649 Cov.: 63 AF XY: 0.523 AC XY: 380276 AN XY: 726548

African (AFR) AF: 0.240 AC: 8032 AN: 33478

American (AMR) AF: 0.299 AC: 13349 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12450 AN: 26132

East Asian (EAS) AF: 0.244 AC: 9694 AN: 39700

South Asian (SAS) AF: 0.347 AC: 29912 AN: 86256

European-Finnish (FIN) AF: 0.613 AC: 31915 AN: 52046

Middle Eastern (MID) AF: 0.389 AC: 2246 AN: 5768

European-Non Finnish (NFE) AF: 0.569 AC: 632402 AN: 1111948

Other (OTH) AF: 0.492 AC: 29729 AN: 60386

GnomAD4 genome AF: 0.439 AC: 66834 AN: 152150 Hom.: 16493 Cov.: 33 AF XY: 0.437 AC XY: 32480 AN XY: 74400

African (AFR) AF: 0.249 AC: 10330 AN: 41508

American (AMR) AF: 0.346 AC: 5293 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3470

East Asian (EAS) AF: 0.260 AC: 1340 AN: 5162

South Asian (SAS) AF: 0.325 AC: 1570 AN: 4824

European-Finnish (FIN) AF: 0.628 AC: 6651 AN: 10590

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38542 AN: 67980

Other (OTH) AF: 0.436 AC: 921 AN: 2114

Alfa AF: 0.508 Hom.: 86756

Bravo AF: 0.412

TwinsUK AF: 0.577 AC: 2141

ALSPAC AF: 0.578 AC: 2227

ESP6500AA AF: 0.258 AC: 1138

ESP6500EA AF: 0.548 AC: 4715

ExAC AF: 0.454 AC: 55051

Asia WGS AF: 0.289 AC: 1004 AN: 3478

EpiCase AF: 0.542

EpiControl AF: 0.541

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Microphthalmia with brain and digit anomalies (3)
-	-	2	not provided (2)
-	-	1	Cleft Lip +/- Cleft Palate, Autosomal Dominant (1)
-	-	1	Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 (1)
-	-	1	Orofacial cleft 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.00011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.067
Sift	Benign	0.40	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.037
MPC		0.59
ClinPred		0.017	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.24
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17563; hg19: chr14-54417522; COSMIC: COSV55416014; COSMIC: COSV55416014;