22-30264283-G-A

Position:

• chr22-30264283-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020530.6(OSM):​c.359C>T​(p.Ala120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OSM NM_020530.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.358

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07928425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSM	NM_020530.6	c.359C>T	p.Ala120Val	missense_variant	3/3	ENST00000215781.3	NP_065391.1
OSM	NM_001319108.2	c.296C>T	p.Ala99Val	missense_variant	3/3		NP_001306037.1
OSM	XM_047441387.1	c.296C>T	p.Ala99Val	missense_variant	3/3		XP_047297343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSM	ENST00000215781.3	c.359C>T	p.Ala120Val	missense_variant	3/3	1	NM_020530.6	ENSP00000215781.2
OSM	ENST00000403389.1	c.296C>T	p.Ala99Val	missense_variant	3/3	3		ENSP00000383893.1
OSM	ENST00000403463.1	c.*153C>T		3_prime_UTR_variant	2/2	3		ENSP00000384543.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jun 29, 2023

The c.359C>T (p.A120V) 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 359, causing the alanine (A) at amino acid position 120 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	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.9
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.049
Sift	Uncertain	0.024	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.057	B;.
Vest4		0.027
MutPred		0.54		Gain of loop (P = 0.002);.;
MVP		0.35
MPC		0.20
ClinPred		0.053	T
GERP RS		-1.4
Varity_R		0.15
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1221481020; hg19: chr22-30660272;