chr20-3082764-G-A

Position:

• chr20-3082764-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Moderate BP6_Moderate

The NM_000490.5(AVP):​c.361C>T​(p.His121Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,269,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. H121H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AVP NM_000490.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a chain Neurophysin 2 (size 92) in uniprot entity NEU2_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000490.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.11765227).
• BP6: Variant 20-3082764-G-A is Benign according to our data. Variant chr20-3082764-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2047616.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVP	NM_000490.5	c.361C>T	p.His121Tyr	missense_variant	3/3	ENST00000380293.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVP	ENST00000380293.3	c.361C>T	p.His121Tyr	missense_variant	3/3	1	NM_000490.5	P1

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151500 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000921

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

GnomAD4 exome AF: 0.00000895 AC: 10 AN: 1117794 Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 3 AN XY: 536974

Gnomad4 AFR exome AF: 0.000355

Gnomad4 AMR exome AF: 0.000109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151608 Hom.: 0 Cov.: 34 AF XY: 0.000337 AC XY: 25 AN XY: 74094

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000920

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000268

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0070	B
Vest4		0.098
MutPred		0.29		Loss of MoRF binding (P = 0.1488);
MVP		0.96
MPC		0.65
ClinPred		0.087	T
GERP RS		1.2
Varity_R		0.044
gMVP		0.29

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

Other links and lift over

dbSNP: rs568253217; hg19: chr20-3063410;