rs755496785

Variant names:

• chr5-38885447-T-C
• rs755496785
• NM_003999.3:c.802T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003999.3(OSMR):​c.802T>C​(p.Ser268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.61
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04129219).

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.802T>C	p.Ser268Pro	missense	Exon 6 of 18	NP_003990.1	Q99650-1
	OSMR	NM_001323506.2		c.802T>C	p.Ser268Pro	missense	Exon 6 of 18	NP_001310435.1
	OSMR	NM_001323505.2		c.802T>C	p.Ser268Pro	missense	Exon 6 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.802T>C	p.Ser268Pro	missense	Exon 6 of 18	ENSP00000274276.3	Q99650-1
	OSMR	ENST00000502536.5	TSL:1	c.802T>C	p.Ser268Pro	missense	Exon 6 of 7	ENSP00000422023.1	Q99650-2
	OSMR	ENST00000880314.1		c.802T>C	p.Ser268Pro	missense	Exon 6 of 18	ENSP00000550373.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251154 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: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461730 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111884

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.085
DANN	Benign	0.24
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.032
Sift	Benign	0.85	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.39		Gain of glycosylation at S268 (P = 0.0665)
MVP		0.36
MPC		0.11
ClinPred		0.024	T
GERP RS		-3.6
Varity_R		0.065
gMVP		0.74
Mutation Taster		=94/6	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: rs755496785; hg19: chr5-38885549;