rs387907103

Variant names:

• chr8-56978137-G-A
• rs387907103
• NM_017813.5:c.559C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-56978137-G-A
• chr8-56978137-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017813.5(BPNT2):​c.559C>T​(p.Arg187*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000964 in 1,452,518 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BPNT2 NM_017813.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.16
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-56978137-G-A is Pathogenic according to our data. Variant chr8-56978137-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.559C>T	p.Arg187*	stop_gained	Exon 3 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.559C>T	p.Arg187*	stop_gained	Exon 3 of 5	ENSP00000262644.4
	BPNT2	ENST00000520392.1	TSL:2	n.85C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000428617.1
	BPNT2	ENST00000517461.1	TSL:5	c.201+2022C>T		intron	N/A	ENSP00000430185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000964 AC: 14 AN: 1452518 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 723184

African (AFR) AF: 0.0000300 AC: 1 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1104336

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000296 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Chondrodysplasia with joint dislocations, gPAPP type (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.2
Vest4		0.38
GERP RS		6.0
Mutation Taster		=4/196	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: rs387907103; hg19: chr8-57890696; COSMIC: COSV52906942;