8-56957996-G-A

Variant names:

• chr8-56957996-G-A
• rs187795495
• NM_017813.5:c.*5797C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_017813.5(BPNT2):​c.*5797C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: BPNT2 NM_017813.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 8-56957996-G-A is Benign according to our data. Variant chr8-56957996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 910250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00104 (158/152238) while in subpopulation AMR AF = 0.00419 (64/15288). AF 95% confidence interval is 0.00336. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPNT2	NM_017813.5	c.*5797C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000262644.9	NP_060283.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BPNT2	ENST00000262644.9	c.*5797C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_017813.5	ENSP00000262644.4

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00191

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74426

African (AFR) AF: 0.000217 AC: 9 AN: 41542

American (AMR) AF: 0.00419 AC: 64 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chondrodysplasia with joint dislocations, gPAPP type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.4
DANN	Benign	0.76
PhyloP100		-0.034
Mutation Taster		=100/0	polymorphism

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: rs187795495; hg19: chr8-57870555;