rs387906821

Positions:

• chr5-38924491-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_003999.3(OSMR):​c.1940A>T​(p.Asp647Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.416

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 7 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 NM_003999.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 5-38924491-A-T is Pathogenic according to our data. Variant chr5-38924491-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 30220.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSMR	NM_003999.3	c.1940A>T	p.Asp647Val	missense_variant	14/18	ENST00000274276.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSMR	ENST00000274276.8	c.1940A>T	p.Asp647Val	missense_variant	14/18	1	NM_003999.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.88	P
Vest4		0.79
MutPred		0.70		Gain of methylation at K646 (P = 0.0297);
MVP		0.71
MPC		0.22
ClinPred		0.90	D
GERP RS		3.6
Varity_R		0.27
gMVP		0.55

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: rs387906821; hg19: chr5-38924593;