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. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 31092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPNT2	NM_017813.5	c.559C>T	p.Arg187*	stop_gained	Exon 3 of 5	ENST00000262644.9	NP_060283.3
BPNT2	XM_047421917.1	c.559C>T	p.Arg187*	stop_gained	Exon 3 of 5		XP_047277873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BPNT2	ENST00000262644.9	c.559C>T	p.Arg187*	stop_gained	Exon 3 of 5	1	NM_017813.5	ENSP00000262644.4
BPNT2	ENST00000517461.1	c.201+2022C>T		intron_variant	Intron 2 of 2	5		ENSP00000430185.1
BPNT2	ENST00000520392.1	n.85C>T		non_coding_transcript_exon_variant	Exon 2 of 5	2		ENSP00000428617.1

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

Gnomad4 AFR exome AF: 0.0000300

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: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000308 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chondrodysplasia with joint dislocations, gPAPP type Pathogenic:3

Oct 23, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 29, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 30, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R187X variant in the IMPAD1 gene has been reported previously in the homozygous state in two unrelated individuals with IMPAD1-related disorder (Vissers et al., 2011; Nizon et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R187X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R187X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.38
GERP RS		6.0

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: rs387907103; hg19: chr8-57890696; COSMIC: COSV52906942;