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GeneBe

6-55774205-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021073.4(BMP5):c.871A>G(p.Arg291Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BMP5
NM_021073.4 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73
Variant links:
Genes affected
BMP5 (HGNC:1072): (bone morphogenetic protein 5) 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. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BMP5NM_021073.4 linkuse as main transcriptc.871A>G p.Arg291Gly missense_variant 4/7 ENST00000370830.4
BMP5NM_001329754.2 linkuse as main transcriptc.871A>G p.Arg291Gly missense_variant 4/6
BMP5NM_001329756.2 linkuse as main transcriptc.871A>G p.Arg291Gly missense_variant 4/5
BMP5XM_011514817.4 linkuse as main transcriptc.871A>G p.Arg291Gly missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMP5ENST00000370830.4 linkuse as main transcriptc.871A>G p.Arg291Gly missense_variant 4/71 NM_021073.4 P1P22003-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461044
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2023The c.871A>G (p.R291G) alteration is located in exon 4 (coding exon 4) of the BMP5 gene. This alteration results from a A to G substitution at nucleotide position 871, causing the arginine (R) at amino acid position 291 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
Cadd
Benign
18
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Benign
-0.87
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Uncertain
0.31
Sift
Benign
0.089
T
Sift4G
Benign
0.20
T
Polyphen
0.11
B
Vest4
0.87
MutPred
0.62
Loss of MoRF binding (P = 0.0263);
MVP
0.67
MPC
0.45
ClinPred
0.92
D
GERP RS
1.8
Varity_R
0.46
gMVP
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs995450354; hg19: chr6-55639003; API