1-39763752-C-G

Variant names:

• chr1-39763752-C-G
• rs775172302
• NM_001720.5:c.908G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001720.5(BMP8B):​c.908G>C​(p.Arg303Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R303Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BMP8B NM_001720.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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]

ACMG classification

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, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP8B	NM_001720.5	c.908G>C	p.Arg303Pro	missense_variant	Exon 5 of 7	ENST00000372827.8	NP_001711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP8B	ENST00000372827.8	c.908G>C	p.Arg303Pro	missense_variant	Exon 5 of 7	1	NM_001720.5	ENSP00000361915.3
PPIE	ENST00000372830.5	c.*91C>G		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361918.1
PPIE	ENST00000356511.6	c.*10C>G		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000348904.2
PPIE	ENST00000467741.2	n.464C>G		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1454926 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 723582

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.74		Loss of solvent accessibility (P = 0.1144);
MVP		0.89
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.93

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

Other links and lift over

dbSNP: rs775172302; hg19: chr1-40229424;