chr20-3082703-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000490.5(AVP):​c.422C>T​(p.Ala141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,290,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AVP
NM_000490.5 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.563
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.23464966).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AVPNM_000490.5 linkc.422C>T p.Ala141Val missense_variant Exon 3 of 3 ENST00000380293.3 NP_000481.2 P01185X5DQP6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AVPENST00000380293.3 linkc.422C>T p.Ala141Val missense_variant Exon 3 of 3 1 NM_000490.5 ENSP00000369647.3 P01185

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
151878
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
10426
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000176
AC:
20
AN:
1138458
Hom.:
0
Cov.:
32
AF XY:
0.0000146
AC XY:
8
AN XY:
548608
show subpopulations
Gnomad4 AFR exome
AF:
0.000434
AC:
10
AN:
23030
Gnomad4 AMR exome
AF:
0.000103
AC:
1
AN:
9690
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
15420
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
25898
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
36390
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
24970
Gnomad4 NFE exome
AF:
0.00
AC:
0
AN:
954274
Gnomad4 Remaining exome
AF:
0.000197
AC:
9
AN:
45730
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
151986
Hom.:
0
Cov.:
34
AF XY:
0.000148
AC XY:
11
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000530
AC:
0.000529814
AN:
0.000529814
Gnomad4 AMR
AF:
0.0000655
AC:
0.0000654965
AN:
0.0000654965
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.00
AC:
0
AN:
0
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.000144

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurohypophyseal diabetes insipidus Uncertain:1
Apr 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Aug 19, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with AVP-related conditions. 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. 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. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 141 of the AVP protein (p.Ala141Val). This variant is present in population databases (rs566930108, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.80
T
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.23
T
MetaSVM
Uncertain
0.22
D
MutationAssessor
Uncertain
2.1
M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.62
N
REVEL
Benign
0.26
Sift
Uncertain
0.021
D
Sift4G
Benign
0.20
T
Polyphen
0.31
B
Vest4
0.29
MutPred
0.38
Loss of disorder (P = 0.0457);
MVP
0.99
MPC
0.77
ClinPred
0.80
D
GERP RS
3.3
Varity_R
0.13
gMVP
0.26
Mutation Taster
=90/10
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs566930108; hg19: chr20-3063349; API