chr22-30264220-G-A

Position:

chr22-30264220-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020530.6(OSM):c.422C>T(p.Pro141Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P141R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 1 hom. )

Consequence

OSM
NM_020530.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.25

Variant links:

Genes affected

OSM (HGNC:8506): (oncostatin M) This gene encodes a member of the leukemia inhibitory factor/oncostatin-M (LIF/OSM) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein is a secreted cytokine and growth regulator that inhibits the proliferation of a number of tumor cell lines. This protein also regulates the production of other cytokines, including interleukin 6, granulocyte-colony stimulating factor and granulocyte-macrophage colony stimulating factor in endothelial cells. This gene and the related gene, leukemia inhibitory factor, also present on chromosome 22, may have resulted from the duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

OSM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014264196).

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
OSM	NM_020530.6 linkuse as main transcript	c.422C>T	p.Pro141Leu	missense_variant	3/3	ENST00000215781.3
OSM	NM_001319108.2 linkuse as main transcript	c.359C>T	p.Pro120Leu	missense_variant	3/3
OSM	XM_047441387.1 linkuse as main transcript	c.359C>T	p.Pro120Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
OSM	ENST00000215781.3 linkuse as main transcript	c.422C>T	p.Pro141Leu	missense_variant	3/3	1	NM_020530.6	P2
OSM	ENST00000403389.1 linkuse as main transcript	c.359C>T	p.Pro120Leu	missense_variant	3/3	3		A2
OSM	ENST00000403463.1 linkuse as main transcript	c.*216C>T		3_prime_UTR_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000358

AC:

AN:

251092

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000432

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000430

AC:

629

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000459

AC XY:

334

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000375

Gnomad4 NFE exome

AF:

0.000464

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000394

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000436

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.422C>T (p.P141L) alteration is located in exon 3 (coding exon 3) of the OSM gene. This alteration results from a C to T substitution at nucleotide position 422, causing the proline (P) at amino acid position 141 to be replaced by a leucine (L). 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

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.025

DANN

Benign

0.82

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.40

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.80

N;N

REVEL

Benign

0.021

Sift

Benign

0.68

T;T

Sift4G

Benign

0.94

T;T

Polyphen

0.0010

B;.

Vest4

0.037

MVP

0.30

MPC

0.17

ClinPred

0.0074

GERP RS

-6.3

Varity_R

0.069

gMVP

0.34

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over