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GeneBe

9-92386262-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014057.5(OGN):c.665A>G(p.His222Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

OGN
NM_014057.5 missense

Scores

12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64
Variant links:
Genes affected
OGN (HGNC:8126): (osteoglycin) This gene encodes a member of the small leucine-rich proteoglycan (SLRP) family of proteins. The encoded protein induces ectopic bone formation in conjunction with transforming growth factor beta and may regulate osteoblast differentiation. High expression of the encoded protein may be associated with elevated heart left ventricular mass. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OGNNM_014057.5 linkuse as main transcriptc.665A>G p.His222Arg missense_variant 6/7 ENST00000375561.10
CENPPNM_001012267.3 linkuse as main transcriptc.564+6403T>C intron_variant ENST00000375587.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OGNENST00000375561.10 linkuse as main transcriptc.665A>G p.His222Arg missense_variant 6/71 NM_014057.5 P1
CENPPENST00000375587.8 linkuse as main transcriptc.564+6403T>C intron_variant 1 NM_001012267.3 P1Q6IPU0-1
OGNENST00000262551.8 linkuse as main transcriptc.665A>G p.His222Arg missense_variant 6/75 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461382
Hom.:
0
Cov.:
29
AF XY:
0.00000413
AC XY:
3
AN XY:
727018
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 14, 2023The c.665A>G (p.H222R) alteration is located in exon 6 (coding exon 5) of the OGN gene. This alteration results from a A to G substitution at nucleotide position 665, causing the histidine (H) at amino acid position 222 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Benign
-0.10
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Benign
0.058
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Uncertain
0.018
D
MutationAssessor
Benign
0.66
N;N
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.026
D;D
Sift4G
Benign
0.066
T;T
Polyphen
0.96
D;D
Vest4
0.54
MutPred
0.41
Loss of catalytic residue at N223 (P = 0.0604);Loss of catalytic residue at N223 (P = 0.0604);
MVP
0.92
MPC
0.74
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.48
gMVP
0.69

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1300279984; hg19: chr9-95148544; API