1-39763764-T-C

Variant names:

• chr1-39763764-T-C
• rs1350314293
• NM_001720.5:c.896A>G

Variant summary

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

The NM_001720.5(BMP8B):​c.896A>G​(p.Gln299Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMP8B NM_001720.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP8B	NM_001720.5	c.896A>G	p.Gln299Arg	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.896A>G	p.Gln299Arg	missense_variant	Exon 5 of 7	1	NM_001720.5	ENSP00000361915.3
PPIE	ENST00000372830.5	c.*103T>C		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361918.1
PPIE	ENST00000356511.6	c.*22T>C		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000348904.2
PPIE	ENST00000467741.2	n.476T>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249684 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454942 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 723604

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.896A>G (p.Q299R) alteration is located in exon 5 (coding exon 5) of the BMP8B gene. This alteration results from a A to G substitution at nucleotide position 896, causing the glutamine (Q) at amino acid position 299 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	-0.21	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.38
Sift	Benign	0.31	T
Sift4G	Benign	0.39	T
Polyphen		0.59	P
Vest4		0.54
MutPred		0.52		Gain of catalytic residue at Q299 (P = 0.0486);
MVP		0.83
ClinPred		0.37	T
GERP RS		1.7
Varity_R		0.11
gMVP		0.62

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: rs1350314293; hg19: chr1-40229436;