GeneBe

rs121964883

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000490.5(AVP):​c.143G>T​(p.Gly48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

AVP
NM_000490.5 missense

Scores

6
7
5

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.10

Publications

5 publications found
Variant links:
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]
AVP Gene-Disease associations (from GenCC):
  • neurohypophyseal diabetes insipidus
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000490.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.0546 (below the threshold of 3.09). Trascript score misZ: -1.717 (below the threshold of 3.09). GenCC associations: The gene is linked to neurohypophyseal diabetes insipidus.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 20-3083156-C-A is Pathogenic according to our data. Variant chr20-3083156-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12205.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000490.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AVP
NM_000490.5
MANE Select
c.143G>Tp.Gly48Val
missense
Exon 2 of 3NP_000481.2

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AVP
ENST00000380293.3
TSL:1 MANE Select
c.143G>Tp.Gly48Val
missense
Exon 2 of 3ENSP00000369647.3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1354910
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
668838
African (AFR)
AF:
0.00
AC:
0
AN:
28008
American (AMR)
AF:
0.00
AC:
0
AN:
32912
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23998
East Asian (EAS)
AF:
0.00
AC:
0
AN:
31588
South Asian (SAS)
AF:
0.00
AC:
0
AN:
76518
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34090
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4686
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1066762
Other (OTH)
AF:
0.00
AC:
0
AN:
56348
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Neurohypophyseal diabetes insipidus Pathogenic:1
Nov 01, 1996
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D
Eigen
Benign
0.037
Eigen_PC
Benign
-0.028
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.87
D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Uncertain
2.4
M
PhyloP100
1.1
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-4.3
D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.020
D
Sift4G
Benign
0.075
T
Polyphen
0.96
D
Vest4
0.77
MutPred
0.84
Loss of disorder (P = 0.0154)
MVP
1.0
MPC
1.6
ClinPred
0.96
D
GERP RS
2.8
Varity_R
0.45
gMVP
0.87
Mutation Taster
=36/64
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs121964883; hg19: chr20-3063802; API