chr10-5374095-C-A

Variant names:

• chr10-5374095-C-A
• rs782110045
• NM_053049.4:c.375C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_053049.4(UCN3):​c.375C>A​(p.Asp125Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D125D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UCN3 NM_053049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCN3	NM_053049.4	MANE Select	c.375C>A	p.Asp125Glu	missense	Exon 2 of 2	NP_444277.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCN3	ENST00000380433.5	TSL:1 MANE Select	c.375C>A	p.Asp125Glu	missense	Exon 2 of 2	ENSP00000369798.3	Q969E3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.36		Loss of catalytic residue at D125 (P = 0.1115)
MVP		0.68
MPC		0.28
ClinPred		0.98	D
GERP RS		-4.7
Varity_R		0.54
gMVP		0.53
Mutation Taster		=53/47	polymorphism

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: rs782110045; hg19: chr10-5416058;