20-3083156-C-G

Variant names:

• chr20-3083156-C-G
• rs121964883
• NM_000490.5:c.143G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000490.5(AVP):​c.143G>C​(p.Gly48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G48V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AVP NM_000490.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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.

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	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVP	NM_000490.5	MANE Select	c.143G>C	p.Gly48Ala	missense	Exon 2 of 3	NP_000481.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVP	ENST00000380293.3	TSL:1 MANE Select	c.143G>C	p.Gly48Ala	missense	Exon 2 of 3	ENSP00000369647.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.39
Sift	Benign	0.037	D
Sift4G	Benign	0.23	T
Polyphen		0.20	B
Vest4		0.32
MutPred		0.58		Loss of disorder (P = 0.1064)
MVP		0.99
MPC		1.1
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.24
gMVP		0.78
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121964883; hg19: chr20-3063802;