chr22-30264067-C-T

Variant names:

• chr22-30264067-C-T
• rs1051631148
• NM_020530.6:c.575G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The NM_020530.6(OSM):​c.575G>A​(p.Cys192Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,595,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: OSM NM_020530.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a mutagenesis_site Inactive. (size 0) in uniprot entity ONCM_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020530.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSM	NM_020530.6	MANE Select	c.575G>A	p.Cys192Tyr	missense	Exon 3 of 3	NP_065391.1	P13725
	OSM	NM_001319108.2		c.512G>A	p.Cys171Tyr	missense	Exon 3 of 3	NP_001306037.1	B5MCX1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSM	ENST00000215781.3	TSL:1 MANE Select	c.575G>A	p.Cys192Tyr	missense	Exon 3 of 3	ENSP00000215781.2	P13725
	OSM	ENST00000403389.1	TSL:3	c.512G>A	p.Cys171Tyr	missense	Exon 3 of 3	ENSP00000383893.1	B5MCX1
	OSM	ENST00000403463.1	TSL:3	c.*369G>A		downstream_gene	N/A	ENSP00000384543.1	B5MC70

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 239936 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1443432 Hom.: 0 Cov.: 31 AF XY: 0.0000126 AC XY: 9 AN XY: 715386

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.0000830 AC: 7 AN: 84302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52598

Middle Eastern (MID) AF: 0.000882 AC: 5 AN: 5668

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1100344

Other (OTH) AF: 0.0000336 AC: 2 AN: 59532

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.89		Gain of methylation at K188 (P = 0.0739)
MVP		0.80
MPC		0.92
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.91
gMVP		0.50
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs1051631148; hg19: chr22-30660056;