9-92416988-G-A

Position:

• chr9-92416988-G-A

Variant summary

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

The NM_005014.3(OMD):​c.571C>T​(p.Leu191Phe) 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: OMD NM_005014.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

Genes affected

OMD (HGNC:8134): (osteomodulin) Predicted to be involved in cell adhesion and regulation of bone mineralization. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OMD	NM_005014.3	c.571C>T	p.Leu191Phe	missense_variant	2/3	ENST00000375550.5
CENPP	NM_001012267.3	c.564+37129G>A		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OMD	ENST00000375550.5	c.571C>T	p.Leu191Phe	missense_variant	2/3	1	NM_005014.3	P1
CENPP	ENST00000375587.8	c.564+37129G>A		intron_variant		1	NM_001012267.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.571C>T (p.L191F) alteration is located in exon 2 (coding exon 1) of the OMD gene. This alteration results from a C to T substitution at nucleotide position 571, causing the leucine (L) at amino acid position 191 to be replaced by a phenylalanine (F). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.62		Gain of catalytic residue at L191 (P = 0.0442);
MVP		0.75
MPC		0.64
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.46

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: rs1843633813; hg19: chr9-95179270;