Genetic Variant OS9:p.His81Asp (chr12-57694828-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006812.4(OS9):c.241C>G(p.His81Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OS9
NM_006812.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.37

Publications

0 publications found

Variant links:

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 links:

ENSG00000257342 (HGNC:58278):

ENSG00000257342 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OS9	NM_006812.4 link	c.241C>G	p.His81Asp	missense_variant	Exon 2 of 15	ENST00000315970.12	NP_006803.1	Q13438-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OS9	ENST00000315970.12 link	c.241C>G	p.His81Asp	missense_variant	Exon 2 of 15	1	NM_006812.4	ENSP00000318165.7		Q13438-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.241C>G (p.H81D) alteration is located in exon 2 (coding exon 2) of the OS9 gene. This alteration results from a C to G substitution at nucleotide position 241, causing the histidine (H) at amino acid position 81 to be replaced by an aspartic acid (D). 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

0.49

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.22

.;T;T;.;T;.;.;.;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.017

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;.;L;.;L;L;L;.;L

PhyloP100

3.4

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.81

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.14

T;T;T;T;T;T;T;T;T;T

Sift4G

Uncertain

0.016

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99, 0.17

.;D;.;.;B;.;.;.;.;.

Vest4

0.46

MutPred

0.29

Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);Gain of disorder (P = 0.0521);

MVP

0.71

MPC

0.39

ClinPred

0.59

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.45

Mutation Taster

=81/19

polymorphism

(source)

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

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12-57694828-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over