chr8-56958288-T-C

Variant names:

• chr8-56958288-T-C
• rs8718
• NM_017813.5:c.*5505A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017813.5(BPNT2):​c.*5505A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 152,188 control chromosomes in the GnomAD database, including 59,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59564 hom., cov: 31)
  • Exomes 𝑓: 0.97 (17 hom.)
• Consequence: BPNT2 NM_017813.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-56958288-T-C is Benign according to our data. Variant chr8-56958288-T-C is described in ClinVar as [Benign]. Clinvar id is 363327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPNT2	NM_017813.5	c.*5505A>G		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.*5505A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_017813.5	ENSP00000262644.4

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134486 AN: 152034 Hom.: 59518 Cov.: 31

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.939

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.882

GnomAD4 exome AF: 0.972 AC: 35 AN: 36 Hom.: 17 Cov.: 0 AF XY: 0.967 AC XY: 29 AN XY: 30

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.964 AC: 27 AN: 28

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.885 AC: 134590 AN: 152152 Hom.: 59564 Cov.: 31 AF XY: 0.884 AC XY: 65754 AN XY: 74374

African (AFR) AF: 0.884 AC: 36676 AN: 41500

American (AMR) AF: 0.920 AC: 14061 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 3259 AN: 3472

East Asian (EAS) AF: 0.885 AC: 4576 AN: 5170

South Asian (SAS) AF: 0.854 AC: 4100 AN: 4800

European-Finnish (FIN) AF: 0.862 AC: 9138 AN: 10596

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.879 AC: 59804 AN: 68016

Other (OTH) AF: 0.884 AC: 1871 AN: 2116

Alfa AF: 0.886 Hom.: 109113

Bravo AF: 0.890

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Chondrodysplasia with joint dislocations, gPAPP type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.62
DANN	Benign	0.54
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs8718; hg19: chr8-57870847;