Genetic Variant ADGRV1:p.Ser3203Pro (chr5-90720207-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032119.4(ADGRV1):c.9607T>C(p.Ser3203Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,400,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S3203T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

Publications

2 publications found

Variant links:

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ADGRV1 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2C
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 4
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ADGRV1 links:

LOC105379077 (HGNC:):

LOC105379077 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3043121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.9607T>C	p.Ser3203Pro	missense_variant	Exon 44 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 link	c.9607T>C	p.Ser3203Pro	missense_variant	Exon 44 of 90	1	NM_032119.4	ENSP00000384582.2		Q8WXG9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000476

AC:

AN:

210020

AF XY:

0.00

show subpopulations

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:

0.00000999

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1400730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692576

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31400

American (AMR)

AF:

0.00

AC:

AN:

36674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24050

East Asian (EAS)

AF:

0.00

AC:

AN:

38424

South Asian (SAS)

AF:

0.00

AC:

AN:

73652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081456

Other (OTH)

AF:

0.00

AC:

AN:

57722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.1

PhyloP100

3.9

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.096

Sift

Benign

0.19

.;T

Sift4G

Benign

0.20

.;T

Polyphen

0.95

P;P

Vest4

0.64

MutPred

0.40

Loss of glycosylation at S3203 (P = 0.1168);Loss of glycosylation at S3203 (P = 0.1168);

MVP

0.67

MPC

0.32

ClinPred

0.64

GERP RS

6.1

Varity_R

0.55

gMVP

0.71

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over