Genetic Variant VIPR1:p.Ala54Asp (chr3-42513831-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004624.4(VIPR1):c.161C>A(p.Ala54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,551,556 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

VIPR1
NM_004624.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.722

Publications

3 publications found

Variant links:

Genes affected

VIPR1 (HGNC:12694): (vasoactive intestinal peptide receptor 1) This gene encodes a receptor for vasoactive intestinal peptide, a small neuropeptide. Vasoactive intestinal peptide is involved in smooth muscle relaxation, exocrine and endocrine secretion, and water and ion flux in lung and intestinal epithelia. Its actions are effected through integral membrane receptors associated with a guanine nucleotide binding protein which activates adenylate cyclase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

VIPR1 links:

VIPR1-AS1 (HGNC:40610): (VIPR1 antisense RNA 1)

VIPR1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005968094).

BS2

High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIPR1	NM_004624.4 link	c.161C>A	p.Ala54Asp	missense_variant	Exon 2 of 13	ENST00000325123.5	NP_004615.2	P32241-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIPR1	ENST00000325123.5 link	c.161C>A	p.Ala54Asp	missense_variant	Exon 2 of 13	1	NM_004624.4	ENSP00000327246.4		P32241-1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00118

AC:

185

AN:

156354

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000390

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.000908

GnomAD4 exome

AF:

0.00254

AC:

3554

AN:

1399288

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1629

AN XY:

690184

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31598

American (AMR)

AF:

0.000168

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.0000795

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

35746

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79218

European-Finnish (FIN)

AF:

0.000609

AC:

AN:

49282

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00315

AC:

3400

AN:

1078898

Other (OTH)

AF:

0.00185

AC:

107

AN:

57988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

192

384

575

767

959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00139

AC:

211

AN:

152268

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41542

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00278

AC:

189

AN:

68014

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00153

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000484

AC:

ESP6500EA

AF:

0.00213

AC:

ExAC

AF:

0.000624

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.161C>A (p.A54D) alteration is located in exon 2 (coding exon 2) of the VIPR1 gene. This alteration results from a C to A substitution at nucleotide position 161, causing the alanine (A) at amino acid position 54 to be replaced by an aspartic acid (D). 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

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.059

.;T;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.45

T;T;T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.0060

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

.;.;.;L

PhyloP100

-0.72

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.22

T;T;T;T

Sift4G

Benign

0.63

T;D;D;T

Polyphen

0.54

.;.;.;P

Vest4

0.20

MVP

0.42

MPC

0.13

ClinPred

0.010

GERP RS

2.3

Varity_R

0.11

gMVP

0.75

Mutation Taster

=91/9

polymorphism

(source)

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

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3-42513831-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over