rs63750567

Positions:

• chr5-38925231-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000274276.8(OSMR):​c.2072T>C​(p.Ile691Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,824 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I691L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OSMR ENST00000274276.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.02

Genes affected

OSMR (HGNC:8507): (oncostatin M receptor) This gene encodes a member of the type I cytokine receptor family. The encoded protein heterodimerizes with interleukin 6 signal transducer to form the type II oncostatin M receptor and with interleukin 31 receptor A to form the interleukin 31 receptor, and thus transduces oncostatin M and interleukin 31 induced signaling events. Mutations in this gene have been associated with familial primary localized cutaneous amyloidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Fibronectin type-III 4 (size 111) in uniprot entity OSMR_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in ENST00000274276.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 5-38925231-T-C is Pathogenic according to our data. Variant chr5-38925231-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7808.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSMR	NM_003999.3	c.2072T>C	p.Ile691Thr	missense_variant	15/18	ENST00000274276.8	NP_003990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSMR	ENST00000274276.8	c.2072T>C	p.Ile691Thr	missense_variant	15/18	1	NM_003999.3	ENSP00000274276	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, primary localized cutaneous, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	2.4e-7	A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.73		Loss of stability (P = 0.0053);
MVP		0.77
MPC		0.51
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.70

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: rs63750567; hg19: chr5-38925333;