rs376960358

Variant names:

• chr14-53951861-T-C
• rs376960358
• NM_001202.6:c.362A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS1

The NM_001202.6(BMP4):​c.362A>G​(p.His121Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,599,388 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H121Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: BMP4 NM_001202.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 7.95
• Publications: 10 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: Likely_benign. The variant received -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.08165255).
• BP6: Variant 14-53951861-T-C is Benign according to our data. Variant chr14-53951861-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 29618.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000122 (177/1447220) while in subpopulation AMR AF = 0.00085 (38/44720). AF 95% confidence interval is 0.000636. There are 1 homozygotes in GnomAdExome4. There are 86 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.362A>G	p.His121Arg	missense	Exon 3 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.503A>G	p.His168Arg	missense	Exon 3 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.362A>G	p.His121Arg	missense	Exon 2 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.362A>G	p.His121Arg	missense	Exon 3 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.362A>G	p.His121Arg	missense	Exon 2 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.362A>G	p.His121Arg	missense	Exon 3 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000343 AC: 82 AN: 238796 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.000122 AC: 177 AN: 1447220 Hom.: 1 Cov.: 32 AF XY: 0.000119 AC XY: 86 AN XY: 720304

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000850 AC: 38 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39270

Middle Eastern (MID) AF: 0.000726 AC: 4 AN: 5512

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111914

Other (OTH) AF: 0.000348 AC: 21 AN: 60270

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000380 AC: 46

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	BMP4-related disorder (1)
1	-	-	Microphthalmia with brain and digit anomalies (1)
-	-	1	Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 (1)
-	-	1	not provided (1)
-	1	-	Orofacial cleft 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.082	T
MetaSVM	Uncertain	0.047	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.73
Sift	Benign	0.045	D
Sift4G	Benign	0.087	T
Polyphen		1.0	D
Vest4		0.85
MVP		0.92
MPC		1.5
ClinPred		0.24	T
GERP RS		5.3
PromoterAI		0.091	Neutral
Varity_R		0.61
gMVP		0.74
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs376960358; hg19: chr14-54418579; COSMIC: COSV55415372; COSMIC: COSV55415372;