rs121912767
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The ENST00000245451.9(BMP4):āc.272C>Gā(p.Ser91Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,609,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00016 ( 0 hom., cov: 33)
Exomes š: 0.00026 ( 0 hom. )
Consequence
BMP4
ENST00000245451.9 missense
ENST00000245451.9 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 7.91
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP6
Variant 14-53951951-G-C is Benign according to our data. Variant chr14-53951951-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17703.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000164 (25/152190) while in subpopulation NFE AF= 0.000367 (25/68042). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BMP4 | NM_001202.6 | c.272C>G | p.Ser91Cys | missense_variant | 3/4 | ENST00000245451.9 | NP_001193.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BMP4 | ENST00000245451.9 | c.272C>G | p.Ser91Cys | missense_variant | 3/4 | 1 | NM_001202.6 | ENSP00000245451 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000182 AC: 45AN: 247294Hom.: 0 AF XY: 0.000172 AC XY: 23AN XY: 134078
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GnomAD4 exome AF: 0.000261 AC: 380AN: 1457618Hom.: 0 Cov.: 32 AF XY: 0.000258 AC XY: 187AN XY: 725380
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Orofacial cleft 11 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 25, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
Microphthalmia with brain and digit anomalies Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 19, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | BMP4: BS2 - |
Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;M;.;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;.;D;.
Polyphen
D;D;D;D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at