dbSNP rs3749737: OSMR:p.Pro936Ser (chr5-38933310-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003999.3(OSMR):c.2806C>T(p.Pro936Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,614,130 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 52 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 147 hom. )

Consequence

OSMR
NM_003999.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.408

Publications

11 publications found

Variant links:

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

OSMR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022120774).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0177 (2701/152286) while in subpopulation AFR AF = 0.0494 (2054/41558). AF 95% confidence interval is 0.0476. There are 52 homozygotes in GnomAd4. There are 1375 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2701 AD,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSMR	NM_003999.3 link	c.2806C>T	p.Pro936Ser	missense_variant	Exon 18 of 18	ENST00000274276.8	NP_003990.1	Q99650-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OSMR	ENST00000274276.8 link	c.2806C>T	p.Pro936Ser	missense_variant	Exon 18 of 18	1	NM_003999.3	ENSP00000274276.3	Q99650-1
OSMR	ENST00000508882.1 link	n.72+775C>T		intron_variant	Intron 1 of 2	3		ENSP00000422372.1	H0Y8W9
OSMR	ENST00000509237.5 link	n.153+775C>T		intron_variant	Intron 2 of 3	5		ENSP00000426729.1	H0YAD1

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2700

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00616

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0483

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.00820

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0110

AC:

2758

AN:

251360

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.0486

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0427

Gnomad FIN exome

AF:

0.00953

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.00914

GnomAD4 exome

AF:

0.00480

AC:

7013

AN:

1461844

Hom.:

147

Cov.:

AF XY:

0.00516

AC XY:

3750

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0505

AC:

1691

AN:

33478

American (AMR)

AF:

0.00318

AC:

142

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0460

AC:

1825

AN:

39700

South Asian (SAS)

AF:

0.0230

AC:

1985

AN:

86258

European-Finnish (FIN)

AF:

0.00874

AC:

467

AN:

53418

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000318

AC:

354

AN:

1111972

Other (OTH)

AF:

0.00873

AC:

527

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

457

914

1370

1827

2284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0177

AC:

2701

AN:

152286

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1375

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0494

AC:

2054

AN:

41558

American (AMR)

AF:

0.00615

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0482

AC:

250

AN:

5190

South Asian (SAS)

AF:

0.0272

AC:

131

AN:

4816

European-Finnish (FIN)

AF:

0.00820

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68026

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00678

Hom.:

Bravo

AF:

0.0187

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0438

AC:

193

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0123

AC:

1494

Asia WGS

AF:

0.0420

AC:

147

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.6

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.11

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

0.41

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

REVEL

Benign

0.040

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.39

Vest4

0.060

MPC

0.19

ClinPred

0.0069

GERP RS

3.8

Varity_R

0.034

gMVP

0.32

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over