5-38925240-C-T

Variant names:

• chr5-38925240-C-T
• rs387906822
• NM_003999.3:c.2081C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PM1 PP5_Very_Strong BS2

The NM_003999.3(OSMR):​c.2081C>T​(p.Pro694Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.97
• Publications: 11 publications found

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]

OSMR Gene-Disease associations (from GenCC):

• amyloidosis, primary localized cutaneous, 1

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• familial primary localized cutaneous amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain Fibronectin type-III 4 (size 111) in uniprot entity OSMR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_003999.3
• PP5: Variant 5-38925240-C-T is Pathogenic according to our data. Variant chr5-38925240-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 12 AD,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSMR	NM_003999.3	c.2081C>T	p.Pro694Leu	missense_variant	Exon 15 of 18	ENST00000274276.8	NP_003990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSMR	ENST00000274276.8	c.2081C>T	p.Pro694Leu	missense_variant	Exon 15 of 18	1	NM_003999.3	ENSP00000274276.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251398 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000175 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, primary localized cutaneous, 1 Pathogenic:2

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PP1_Strong+PP4 -

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 20, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in the heterozygous state, in multiple individuals with familial and sporadic primary cutaneous amyloidosis referred for genetic testing at GeneDx and in published literature (PMID: 23692662, 19690585); Segregates with autosomal dominant familial primary cutaneous amyloidosis in many affected individuals from several families in published literature (PMID: 19690585, 30740762, 19663869); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23742287, 19663869, 19690585, 30740762, 23692662, 29419851, 33502684, 30734345) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.58
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.0
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.34
Sift	Benign	0.86	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.54		Loss of helix (P = 0.0076);
MVP		0.74
MPC		0.47
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.64
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906822; hg19: chr5-38925342; COSMIC: COSV57087799;