rs10904481

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCN3	NM_053049.4	c.271A>G	p.Arg91Gly	missense_variant	Exon 2 of 2	ENST00000380433.5	NP_444277.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCN3	ENST00000380433.5	c.271A>G	p.Arg91Gly	missense_variant	Exon 2 of 2	1	NM_053049.4	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

GnomAD3 exomes AF: 0.371 AC: 88919 AN: 239556 Hom.: 17736 AF XY: 0.375 AC XY: 48666 AN XY: 129654

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 SAS exome AF: 0.536

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

Gnomad4 AFR exome AF: 0.342

Gnomad4 AMR exome AF: 0.473

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.350

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

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.296

Gnomad4 OTH AF: 0.361

Alfa AF: 0.320 Hom.: 17593

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 v4.3

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
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

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

Publications

LitVar

Other links and lift over

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