rs387907102

Variant names:

• chr8-56980038-T-G
• rs387907102
• NM_017813.5:c.547A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_017813.5(BPNT2):​c.547A>C​(p.Thr183Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,444 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BPNT2 NM_017813.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.88
• Publications: 3 publications found

Genes affected

BPNT2 (HGNC:26019): (3'(2'), 5'-bisphosphate nucleotidase 2) This gene encodes a member of the inositol monophosphatase family. The encoded protein is localized to the Golgi apparatus and catalyzes the hydrolysis of phosphoadenosine phosphate (PAP) to adenosine monophosphate (AMP). Mutations in this gene are a cause of GRAPP type chondrodysplasia with joint dislocations, and a pseudogene of this gene is located on the long arm of chromosome 1. [provided by RefSeq, Dec 2011]

BPNT2 Gene-Disease associations (from GenCC):

• chondrodysplasia with joint dislocations, gPAPP type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 8-56980038-T-G is Pathogenic according to our data. Variant chr8-56980038-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31091.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017813.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPNT2	NM_017813.5	MANE Select	c.547A>C	p.Thr183Pro	missense	Exon 2 of 5	NP_060283.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPNT2	ENST00000262644.9	TSL:1 MANE Select	c.547A>C	p.Thr183Pro	missense	Exon 2 of 5	ENSP00000262644.4
	BPNT2	ENST00000520392.1	TSL:2	n.73A>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000428617.1
	BPNT2	ENST00000517461.1	TSL:5	c.201+121A>C		intron	N/A	ENSP00000430185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Chondrodysplasia with joint dislocations, gPAPP type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.74		Loss of phosphorylation at T183 (P = 0.1234)
MVP		0.76
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.97
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907102; hg19: chr8-57892597;