chr5-90653278-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032119.4(ADGRV1):c.3704A>G(p.Asn1235Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1235D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.91

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.3704A>G	p.Asn1235Ser	missense_variant	Exon 20 of 90	ENST00000405460.9	NP_115495.3	Q8WXG9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRV1	ENST00000405460.9 link	c.3704A>G	p.Asn1235Ser	missense_variant	Exon 20 of 90	1	NM_032119.4	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000640403.1 link	c.995A>G	p.Asn332Ser	missense_variant	Exon 10 of 29	5		ENSP00000492531.1	A0A1W2PRC7
ADGRV1	ENST00000504142.2 link	n.2470A>G		non_coding_transcript_exon_variant	Exon 14 of 14	5
ADGRV1	ENST00000639676.1 link	n.1302A>G		non_coding_transcript_exon_variant	Exon 8 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248966

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60372

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1235 of the ADGRV1 protein (p.Asn1235Ser). This variant is present in population databases (rs746622083, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADGRV1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Nov 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn1235Ser variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/11278 of Lat ino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs746622083). However, this frequency is not high enough to rul e out a pathogenic role. Computational prediction tools and conservation analysi s do not provide strong support for or against an impact to the protein. In summ ary, the clinical significance of the p.Asn1235Ser is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-0.82

PhyloP100

5.9

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.9

.;D;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.011

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.44

MVP

0.69

MPC

0.17

ClinPred

0.84

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.75

Mutation Taster

=77/23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over