rs387906822

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-38925240-C-T
• chr5-38925240-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. 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:4
• 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: AD, SD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial primary localized cutaneous amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003999.3. 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
	OSMR	NM_003999.3	MANE Select	c.2081C>T	p.Pro694Leu	missense	Exon 15 of 18	NP_003990.1	Q99650-1
	OSMR	NM_001323506.2		c.2084C>T	p.Pro695Leu	missense	Exon 15 of 18	NP_001310435.1
	OSMR	NM_001323505.2		c.2081C>T	p.Pro694Leu	missense	Exon 15 of 18	NP_001310434.1	Q99650-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSMR	ENST00000274276.8	TSL:1 MANE Select	c.2081C>T	p.Pro694Leu	missense	Exon 15 of 18	ENSP00000274276.3	Q99650-1
	OSMR	ENST00000880314.1		c.2084C>T	p.Pro695Leu	missense	Exon 15 of 18	ENSP00000550373.1
	OSMR	ENST00000880315.1		c.2084C>T	p.Pro695Leu	missense	Exon 15 of 18	ENSP00000550374.1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Amyloidosis, primary localized cutaneous, 1 (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;