NM_003999.3:c.2196G>A

Variant names:

• chr5-38925355-G-A
• rs2289926
• NM_003999.3:c.2196G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003999.3(OSMR):​c.2196G>A​(p.Thr732Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,836 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (123 hom.)
• Consequence: OSMR NM_003999.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.25
• Publications: 6 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 5-38925355-G-A is Benign according to our data. Variant chr5-38925355-G-A is described in ClinVar as Benign. ClinVar VariationId is 779884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSMR	NM_003999.3	MANE Select	c.2196G>A	p.Thr732Thr	synonymous	Exon 15 of 18	NP_003990.1
	OSMR	NM_001323506.2		c.2199G>A	p.Thr733Thr	synonymous	Exon 15 of 18	NP_001310435.1
	OSMR	NM_001323505.2		c.2196G>A	p.Thr732Thr	synonymous	Exon 15 of 18	NP_001310434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSMR	ENST00000274276.8	TSL:1 MANE Select	c.2196G>A	p.Thr732Thr	synonymous	Exon 15 of 18	ENSP00000274276.3

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 517 AN: 152118 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00611 AC: 1536 AN: 251350 AF XY: 0.00560

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0779

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00229 AC: 3341 AN: 1461600 Hom.: 123 Cov.: 32 AF XY: 0.00225 AC XY: 1635 AN XY: 727144

African (AFR) AF: 0.000568 AC: 19 AN: 33474

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.0692 AC: 2747 AN: 39690

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86244

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

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111758

Other (OTH) AF: 0.00603 AC: 364 AN: 60388

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152236 Hom.: 13 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74416

African (AFR) AF: 0.00120 AC: 50 AN: 41544

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0785 AC: 406 AN: 5174

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00204 Hom.: 21

Bravo AF: 0.00347

Asia WGS AF: 0.0340 AC: 117 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.90
DANN	Benign	0.50
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2289926; hg19: chr5-38925457;