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GeneBe

1-39763752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001720.5(BMP8B):c.908G>A(p.Arg303Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 148,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

BMP8B
NM_001720.5 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46
Variant links:
Genes affected
BMP8B (HGNC:1075): (bone morphogenetic protein 8b) 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. The encoded protein stimulates thermogenesis in brown adipose tissue. Expression of this gene may be downregulated in pancreatic cancer. This gene may have arose from a gene duplication event and its gene duplicate is also present on chromosome 1. [provided by RefSeq, Jul 2016]
PPIE (HGNC:9258): (peptidylprolyl isomerase E) The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein contains a highly conserved cyclophilin (CYP) domain as well as an RNA-binding domain. It was shown to possess PPIase and protein folding activities, and it also exhibits RNA-binding activity. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 1, has been identified. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BMP8BNM_001720.5 linkuse as main transcriptc.908G>A p.Arg303Gln missense_variant 5/7 ENST00000372827.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMP8BENST00000372827.8 linkuse as main transcriptc.908G>A p.Arg303Gln missense_variant 5/71 NM_001720.5 P1P34820-1
PPIEENST00000356511.6 linkuse as main transcriptc.*10C>T 3_prime_UTR_variant 10/101 Q9UNP9-2
PPIEENST00000372830.5 linkuse as main transcriptc.*91C>T 3_prime_UTR_variant 11/111 Q9UNP9-3
PPIEENST00000467741.2 linkuse as main transcriptn.464C>T non_coding_transcript_exon_variant 4/43

Frequencies

GnomAD3 genomes
AF:
0.0000134
AC:
2
AN:
148892
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000660
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:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249888
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000687
AC:
10
AN:
1454926
Hom.:
0
Cov.:
34
AF XY:
0.00000829
AC XY:
6
AN XY:
723582
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000778
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000541
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000134
AC:
2
AN:
148892
Hom.:
0
Cov.:
33
AF XY:
0.0000138
AC XY:
1
AN XY:
72716
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000660
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000149
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

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 GeneticsSep 27, 2021The c.908G>A (p.R303Q) alteration is located in exon 5 (coding exon 5) of the BMP8B gene. This alteration results from a G to A substitution at nucleotide position 908, causing the arginine (R) at amino acid position 303 to be replaced by a glutamine (Q). 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
Benign
0.27
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Pathogenic
31
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
0.79
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Benign
0.40
N
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
0.97
D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.3
N
REVEL
Pathogenic
0.65
Sift
Uncertain
0.021
D
Sift4G
Benign
0.12
T
Polyphen
1.0
D
Vest4
0.49
MutPred
0.67
Loss of sheet (P = 0.1501);
MVP
0.91
ClinPred
0.94
D
GERP RS
4.0
Varity_R
0.27
gMVP
0.72

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: rs775172302; hg19: chr1-40229424; API