NM_003999.3:c.1657G>A

Variant names:

• chr5-38921686-G-A
• rs2278329
• NM_003999.3:c.1657G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003999.3(OSMR):​c.1657G>A​(p.Asp553Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,614,124 control chromosomes in the GnomAD database, including 2,723 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.025 (368 hom., cov: 32)
  • Exomes 𝑓: 0.014 (2355 hom.)
• Consequence: OSMR NM_003999.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 23 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004065454).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSMR	NM_003999.3	MANE Select	c.1657G>A	p.Asp553Asn	missense	Exon 12 of 18	NP_003990.1	Q99650-1
	OSMR	NM_001323506.2		c.1660G>A	p.Asp554Asn	missense	Exon 12 of 18	NP_001310435.1
	OSMR	NM_001323505.2		c.1657G>A	p.Asp553Asn	missense	Exon 12 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.1657G>A	p.Asp553Asn	missense	Exon 12 of 18	ENSP00000274276.3	Q99650-1
	OSMR	ENST00000880314.1		c.1660G>A	p.Asp554Asn	missense	Exon 12 of 18	ENSP00000550373.1
	OSMR	ENST00000880315.1		c.1660G>A	p.Asp554Asn	missense	Exon 12 of 18	ENSP00000550374.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3805 AN: 152150 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0329 AC: 8279 AN: 251450 AF XY: 0.0301

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0141 AC: 20542 AN: 1461856 Hom.: 2355 Cov.: 32 AF XY: 0.0137 AC XY: 9942 AN XY: 727232

African (AFR) AF: 0.0353 AC: 1181 AN: 33480

American (AMR) AF: 0.00273 AC: 122 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26134

East Asian (EAS) AF: 0.321 AC: 12751 AN: 39692

South Asian (SAS) AF: 0.0114 AC: 982 AN: 86258

European-Finnish (FIN) AF: 0.00335 AC: 179 AN: 53420

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00323 AC: 3597 AN: 1111984

Other (OTH) AF: 0.0274 AC: 1657 AN: 60396

GnomAD4 genome AF: 0.0251 AC: 3817 AN: 152268 Hom.: 368 Cov.: 32 AF XY: 0.0263 AC XY: 1958 AN XY: 74454

African (AFR) AF: 0.0340 AC: 1411 AN: 41550

American (AMR) AF: 0.00726 AC: 111 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1846 AN: 5160

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4820

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 68032

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0155 Hom.: 692

Bravo AF: 0.0281

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.0330 AC: 4001

Asia WGS AF: 0.144 AC: 499 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00373

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.94	L
PhyloP100		0.025
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.031
Sift	Benign	0.63	T
Sift4G	Benign	0.56	T
Polyphen		0.012	B
Vest4		0.025
MPC		0.10
ClinPred		0.000040	T
GERP RS		1.7
Varity_R		0.081
gMVP		0.19
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2278329; hg19: chr5-38921788; COSMIC: COSV57082505; COSMIC: COSV57082505;