rs34675408

Positions:

• chr5-38883969-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003999.3(OSMR):​c.561T>G​(p.His187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,613,524 control chromosomes in the GnomAD database, including 5,554 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.096 (795 hom., cov: 33)
  • Exomes 𝑓: 0.076 (4759 hom.)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012784004).
• BP6: Variant 5-38883969-T-G is Benign according to our data. Variant chr5-38883969-T-G is described in ClinVar as [Benign]. Clinvar id is 3038218.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-38883969-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSMR	NM_003999.3	c.561T>G	p.His187Gln	missense_variant	5/18	ENST00000274276.8	NP_003990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSMR	ENST00000274276.8	c.561T>G	p.His187Gln	missense_variant	5/18	1	NM_003999.3	ENSP00000274276.3
OSMR	ENST00000502536.5	c.561T>G	p.His187Gln	missense_variant	5/7	1		ENSP00000422023.1

Frequencies

GnomAD3 genomes AF: 0.0958 AC: 14575 AN: 152142 Hom.: 786 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0643

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.0974

GnomAD3 exomes AF: 0.0830 AC: 20842 AN: 251258 Hom.: 1047 AF XY: 0.0851 AC XY: 11563 AN XY: 135796

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.0323

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.0873

GnomAD4 exome AF: 0.0756 AC: 110424 AN: 1461264 Hom.: 4759 Cov.: 32 AF XY: 0.0772 AC XY: 56155 AN XY: 726964

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0511

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.0304

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0994

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0852

GnomAD4 genome AF: 0.0959 AC: 14607 AN: 152260 Hom.: 795 Cov.: 33 AF XY: 0.0971 AC XY: 7233 AN XY: 74454

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.0641

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0739

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0833 Hom.: 919

Bravo AF: 0.0952

TwinsUK AF: 0.0682 AC: 253

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.145 AC: 637

ESP6500EA AF: 0.0749 AC: 644

ExAC AF: 0.0837 AC: 10165

Asia WGS AF: 0.119 AC: 412 AN: 3478

EpiCase AF: 0.0768

EpiControl AF: 0.0763

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

OSMR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.096
DANN	Benign	0.65
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.015
Sift	Benign	0.33	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.010	B;B
Vest4		0.066
MutPred		0.24		Gain of disorder (P = 0.154);Gain of disorder (P = 0.154);
MPC		0.086
ClinPred		0.0018	T
GERP RS		-8.3
Varity_R		0.047
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34675408; hg19: chr5-38884071; COSMIC: COSV57085129;