chr12-57694838-G-C

Position:

• chr12-57694838-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006812.4(OS9):​c.251G>C​(p.Arg84Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OS9 NM_006812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

Genes affected

OS9 (HGNC:16994): (OS9 endoplasmic reticulum lectin) This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

OS9 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.356829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OS9	NM_006812.4	c.251G>C	p.Arg84Pro	missense_variant	2/15	ENST00000315970.12	NP_006803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OS9	ENST00000315970.12	c.251G>C	p.Arg84Pro	missense_variant	2/15	1	NM_006812.4	ENSP00000318165.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jul 27, 2024

The c.251G>C (p.R84P) alteration is located in exon 2 (coding exon 2) of the OS9 gene. This alteration results from a G to C substitution at nucleotide position 251, causing the arginine (R) at amino acid position 84 to be replaced by a proline (P). 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	0.40
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	.;T;T;.;T;.;.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;.;L;.;L;L;L;.;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.022	D;D;T;D;T;D;D;D;T;D
Sift4G	Uncertain	0.045	D;T;D;T;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;D;.;.;.;.;.
Vest4		0.41
MutPred		0.38		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.87
MPC		1.1
ClinPred		0.86	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.60

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: rs1274307056; hg19: chr12-58088621;