chr22-30264118-G-T

Position:

• chr22-30264118-G-T

Variant summary

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

The NM_020530.6(OSM):​c.524C>A​(p.Pro175Gln) 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. 15/21 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: -0.186

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=0.12354475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSM	NM_020530.6	c.524C>A	p.Pro175Gln	missense_variant	3/3	ENST00000215781.3
OSM	NM_001319108.2	c.461C>A	p.Pro154Gln	missense_variant	3/3
OSM	XM_047441387.1	c.461C>A	p.Pro154Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSM	ENST00000215781.3	c.524C>A	p.Pro175Gln	missense_variant	3/3	1	NM_020530.6	P2
OSM	ENST00000403389.1	c.461C>A	p.Pro154Gln	missense_variant	3/3	3		A2
OSM	ENST00000403463.1	c.*318C>A		3_prime_UTR_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Oct 10, 2023

The c.524C>A (p.P175Q) alteration is located in exon 3 (coding exon 3) of the OSM gene. This alteration results from a C to A substitution at nucleotide position 524, causing the proline (P) at amino acid position 175 to be replaced by a glutamine (Q). 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	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.0
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.15
Sift	Benign	0.085	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.99	D;.
Vest4		0.11
MutPred		0.53		Loss of catalytic residue at P175 (P = 0.0155);.;
MVP		0.48
MPC		0.43
ClinPred		0.14	T
GERP RS		1.1
Varity_R		0.033
gMVP		0.20

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

Other links and lift over

dbSNP: rs145296302; hg19: chr22-30660107;