20-3082788-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000490.5(AVP):c.337G>A(p.Glu113Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,253,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: AVP NM_000490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

AVP (HGNC:894): (arginine vasopressin) This gene encodes a member of the vasopressin/oxytocin family and preproprotein that is proteolytically processed to generate multiple protein products. These products include the neuropeptide hormone arginine vasopressin, and two other peptides, neurophysin 2 and copeptin. Arginine vasopressin is a posterior pituitary hormone that is synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus. Along with its carrier protein, neurophysin 2, it is packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis where it is either stored or secreted into the bloodstream. The precursor is thought to be activated while it is being transported along the axon to the posterior pituitary. Arginine vasopressin acts as a growth factor by enhancing pH regulation through acid-base transport systems. It has a direct antidiuretic action on the kidney, and also causes vasoconstriction of the peripheral vessels. This hormone can contract smooth muscle during parturition and lactation. It is also involved in cognition, tolerance, adaptation and complex sexual and maternal behaviour, as well as in the regulation of water excretion and cardiovascular functions. Mutations in this gene cause autosomal dominant neurohypophyseal diabetes insipidus (ADNDI). This gene is present in a gene cluster with the related gene oxytocin on chromosome 20. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000490.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVP	NM_000490.5	c.337G>A	p.Glu113Lys	missense_variant	3/3	ENST00000380293.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVP	ENST00000380293.3	c.337G>A	p.Glu113Lys	missense_variant	3/3	1	NM_000490.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000661 AC: 10 AN: 151394 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000209 AC: 23 AN: 1102272 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 16 AN XY: 527672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000439

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000229

GnomAD4 genome AF: 0.0000661 AC: 10 AN: 151394 Hom.: 0 Cov.: 34 AF XY: 0.0000406 AC XY: 3 AN XY: 73934

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000433 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant has not been reported in the literature in individuals affected with AVP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 113 of the AVP protein (p.Glu113Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.70	P
Vest4		0.16
MutPred		0.60		Gain of ubiquitination at E113 (P = 0.0075);
MVP		0.99
MPC		0.75
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121964889; hg19: chr20-3063434;