12-57694910-C-T

Variant summary

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

The NM_006812.4(OS9):c.323C>T(p.Ala108Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OS9 NM_006812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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]

(HGNC:):

ACMG classification

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
OS9	NM_006812.4	c.323C>T	p.Ala108Val	missense_variant	2/15	ENST00000315970.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OS9	ENST00000315970.12	c.323C>T	p.Ala108Val	missense_variant	2/15	1	NM_006812.4	P4
	ENST00000549477.1	n.535-614G>A		intron_variant, non_coding_transcript_variant		3

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

Dec 09, 2023

The c.323C>T (p.A108V) alteration is located in exon 2 (coding exon 2) of the OS9 gene. This alteration results from a C to T substitution at nucleotide position 323, causing the alanine (A) at amino acid position 108 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M;M;.;M;.;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;N;D;N;D;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.042	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;D;.;.;.;.;.
Vest4		0.50
MutPred		0.54		Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);Loss of ubiquitination at K113 (P = 0.0787);
MVP		0.83
MPC		0.74
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr12-58088693;