chr5-38883919-A-G

Variant names:

• chr5-38883919-A-G
• rs1207409657
• NM_003999.3:c.511A>G

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.511A>G​(p.Arg171Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,676 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.704
• 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: 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: 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=0.056269407).

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.511A>G	p.Arg171Gly	missense	Exon 5 of 18	NP_003990.1	Q99650-1
	OSMR	NM_001323506.2		c.511A>G	p.Arg171Gly	missense	Exon 5 of 18	NP_001310435.1
	OSMR	NM_001323505.2		c.511A>G	p.Arg171Gly	missense	Exon 5 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.511A>G	p.Arg171Gly	missense	Exon 5 of 18	ENSP00000274276.3	Q99650-1
	OSMR	ENST00000502536.5	TSL:1	c.511A>G	p.Arg171Gly	missense	Exon 5 of 7	ENSP00000422023.1	Q99650-2
	OSMR	ENST00000880314.1		c.511A>G	p.Arg171Gly	missense	Exon 5 of 18	ENSP00000550373.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461450 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

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

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111662

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

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	0.066
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.0
DANN	Benign	0.73
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PhyloP100		0.70
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.029
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.082
MVP		0.42
MPC		0.11
ClinPred		0.89	D
GERP RS		0.028
Varity_R		0.062
gMVP		0.38
Mutation Taster		=96/4	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: rs1207409657; hg19: chr5-38884021;