rs372233789

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005014.3(OMD):​c.1007G>T​(p.Arg336Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

OMD
NM_005014.3 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OMDNM_005014.3 linkc.1007G>T p.Arg336Leu missense_variant Exon 3 of 3 ENST00000375550.5 NP_005005.1 Q99983
CENPPNM_001012267.3 linkc.564+35552C>A intron_variant Intron 5 of 7 ENST00000375587.8 NP_001012267.1 Q6IPU0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OMDENST00000375550.5 linkc.1007G>T p.Arg336Leu missense_variant Exon 3 of 3 1 NM_005014.3 ENSP00000364700.4 Q99983
CENPPENST00000375587.8 linkc.564+35552C>A intron_variant Intron 5 of 7 1 NM_001012267.3 ENSP00000364737.3 Q6IPU0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461296
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726968
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:
0.0000117
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.046
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.9
M
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.7
D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.84
MutPred
0.82
Loss of catalytic residue at R336 (P = 0.0317);
MVP
0.78
MPC
0.70
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.84
gMVP
0.67

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: rs372233789; hg19: chr9-95177693; API