rs10904481

Variant names:

• chr10-5373991-A-G
• rs10904481
• NM_053049.4:c.271A>G

Variant summary

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

The NM_053049.4(UCN3):​c.271A>G​(p.Arg91Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,608,508 control chromosomes in the GnomAD database, including 88,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.34 (9053 hom., cov: 29)
  • Exomes 𝑓: 0.32 (79321 hom.)
• Consequence: UCN3 NM_053049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 27 publications found

Genes affected

UCN3 (HGNC:17781): (urocortin 3) This gene encodes a member of the sauvagine/corticotropin-releasing factor/urotensin I family of proteins. The encoded preproprotein is proteolytically processed to generate the mature peptide hormone, which is secreted by pancreatic beta and alpha cells. This hormone is an endogenous ligand for corticotropin-releasing factor receptor 2 and may regulate insulin secretion in response to plasma glucose levels. Patients with type 2 diabetes exhibit reduced levels of the encoded protein in beta cells. In the brain, the encoded protein may be responsible for the effects of stress on appetite. [provided by RefSeq, May 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.094899E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053049.4. 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
	UCN3	NM_053049.4	MANE Select	c.271A>G	p.Arg91Gly	missense	Exon 2 of 2	NP_444277.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCN3	ENST00000380433.5	TSL:1 MANE Select	c.271A>G	p.Arg91Gly	missense	Exon 2 of 2	ENSP00000369798.3

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51084 AN: 151518 Hom.: 9035 Cov.: 29

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.371 AC: 88919 AN: 239556 AF XY: 0.375

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.363

GnomAD4 exome AF: 0.320 AC: 466224 AN: 1456870 Hom.: 79321 Cov.: 57 AF XY: 0.327 AC XY: 236607 AN XY: 724348

African (AFR) AF: 0.342 AC: 11429 AN: 33380

American (AMR) AF: 0.473 AC: 20716 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9586 AN: 26028

East Asian (EAS) AF: 0.526 AC: 20744 AN: 39452

South Asian (SAS) AF: 0.532 AC: 45568 AN: 85612

European-Finnish (FIN) AF: 0.272 AC: 14444 AN: 53106

Middle Eastern (MID) AF: 0.435 AC: 2507 AN: 5766

European-Non Finnish (NFE) AF: 0.289 AC: 320181 AN: 1109606

Other (OTH) AF: 0.350 AC: 21049 AN: 60168

GnomAD4 genome AF: 0.337 AC: 51145 AN: 151638 Hom.: 9053 Cov.: 29 AF XY: 0.346 AC XY: 25658 AN XY: 74102

African (AFR) AF: 0.336 AC: 13877 AN: 41314

American (AMR) AF: 0.440 AC: 6719 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3468

East Asian (EAS) AF: 0.539 AC: 2754 AN: 5110

South Asian (SAS) AF: 0.537 AC: 2567 AN: 4784

European-Finnish (FIN) AF: 0.266 AC: 2812 AN: 10558

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20061 AN: 67836

Other (OTH) AF: 0.361 AC: 759 AN: 2100

Alfa AF: 0.323 Hom.: 28972

Bravo AF: 0.350

TwinsUK AF: 0.272 AC: 1008

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.338 AC: 1489

ESP6500EA AF: 0.296 AC: 2544

ExAC AF: 0.359 AC: 43506

Asia WGS AF: 0.546 AC: 1894 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.6
DANN	Benign	0.10
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00023	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.6	N
PhyloP100		2.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.049
ClinPred		0.0065	T
GERP RS		2.5
Varity_R		0.039
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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: rs10904481; hg19: chr10-5415954; COSMIC: COSV66824058;