Genetic Variant OS9:p.Leu15Phe (chr12-57694204-C-T) – 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.43C>T(p.Leu15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. L15V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OS9
NM_006812.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.546

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=0.108584344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OS9	NM_006812.4 link	c.43C>T	p.Leu15Phe	missense_variant	Exon 1 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.43C>T	p.Leu15Phe	missense_variant	Exon 1 of 15	1	NM_006812.4	ENSP00000318165.7		Q13438-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.24

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.85

T;T;T;D;T;T;D;T;D;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

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

PhyloP100

0.55

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.71

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

REVEL

Benign

0.024

Sift

Benign

0.26

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

Sift4G

Benign

0.075

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

Polyphen

0.0020, 0.0030

.;B;.;.;.;B;.;.;.;.;.

Vest4

0.22

MutPred

0.32

Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);

MVP

0.61

MPC

0.30

ClinPred

0.22

GERP RS

4.1

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.074

gMVP

0.37

Mutation Taster

=77/23

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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12-57694204-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over