Genetic Variant AVPR1B:p.Leu326Ser (chr1-206110487-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000707.5(AVPR1B):c.977T>C(p.Leu326Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

AVPR1B
NM_000707.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

AVPR1B (HGNC:896): (arginine vasopressin receptor 1B) The protein encoded by this gene acts as receptor for arginine vasopressin. This receptor belongs to the subfamily of G-protein coupled receptors which includes AVPR1A, V2R and OXT receptors. Its activity is mediated by G proteins which stimulate a phosphatidylinositol-calcium second messenger system. The receptor is primarily located in the anterior pituitary, where it stimulates ACTH release. It is expressed at high levels in ACTH-secreting pituitary adenomas as well as in bronchial carcinoids responsible for the ectopic ACTH syndrome. A spliced antisense transcript of this gene has been reported but its function is not known. [provided by RefSeq, Jul 2008]

AVPR1B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR1B	NM_000707.5 link	c.977T>C	p.Leu326Ser	missense_variant	Exon 2 of 2	ENST00000367126.5	NP_000698.1	P47901

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR1B	ENST00000367126.5 link	c.977T>C	p.Leu326Ser	missense_variant	Exon 2 of 2	1	NM_000707.5	ENSP00000356094.4		P47901
AVPR1B	ENST00000612906.1 link	n.73T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000428

AC:

107

AN:

250182

Hom.:

AF XY:

0.000444

AC XY:

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000832

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000730

AC:

1066

AN:

1461102

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000903

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000342

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000655

Hom.:

Bravo

AF:

0.000363

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.977T>C (p.L326S) alteration is located in exon 2 (coding exon 2) of the AVPR1B gene. This alteration results from a T to C substitution at nucleotide position 977, causing the leucine (L) at amino acid position 326 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

LIST_S2

Pathogenic

0.98

MetaRNN

Pathogenic

0.91

PROVEAN

Pathogenic

-5.3

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.98

gMVP

0.99

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over