9-92385755-G-T

Variant names:

• chr9-92385755-G-T
• NM_014057.5:c.762C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014057.5(OGN):​c.762C>A​(p.Phe254Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: OGN NM_014057.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGN	NM_014057.5	c.762C>A	p.Phe254Leu	missense_variant	Exon 7 of 7	ENST00000375561.10	NP_054776.1
CENPP	NM_001012267.3	c.564+5896G>T		intron_variant	Intron 5 of 7	ENST00000375587.8	NP_001012267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OGN	ENST00000375561.10	c.762C>A	p.Phe254Leu	missense_variant	Exon 7 of 7	1	NM_014057.5	ENSP00000364711.5
CENPP	ENST00000375587.8	c.564+5896G>T		intron_variant	Intron 5 of 7	1	NM_001012267.3	ENSP00000364737.3
OGN	ENST00000262551.8	c.762C>A	p.Phe254Leu	missense_variant	Exon 7 of 7	5		ENSP00000262551.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.762C>A (p.F254L) alteration is located in exon 7 (coding exon 6) of the OGN gene. This alteration results from a C to A substitution at nucleotide position 762, causing the phenylalanine (F) at amino acid position 254 to be replaced by a leucine (L). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.70		Gain of catalytic residue at F254 (P = 0.0634);Gain of catalytic residue at F254 (P = 0.0634);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.89
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-95148037;