5-90745264-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032119.4(ADGRV1):c.10768A>T(p.Ser3590Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,567,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 2 hom. )

Consequence

ADGRV1
NM_032119.4 missense, splice_region

Scores

Splicing: ADA: 0.9784

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.50

Publications

3 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03485784).

BP6

Variant 5-90745264-A-T is Benign according to our data. Variant chr5-90745264-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505525.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.10768A>T	p.Ser3590Cys	missense splice_region	Exon 51 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.10784A>T		splice_region non_coding_transcript_exon	Exon 51 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.10768A>T	p.Ser3590Cys	missense splice_region	Exon 51 of 90	ENSP00000384582.2
ADGRV1	ENST00000509621.1	TSL:1	n.3465A>T		splice_region non_coding_transcript_exon	Exon 19 of 26
ADGRV1	ENST00000640374.1	TSL:5	n.3912A>T		splice_region non_coding_transcript_exon	Exon 21 of 27

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.000227

AC:

AN:

224386

AF XY:

0.000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.000370

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1415644

Hom.:

Cov.:

AF XY:

0.0000712

AC XY:

AN XY:

702498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32020

American (AMR)

AF:

0.00116

AC:

AN:

39818

Ashkenazi Jewish (ASJ)

AF:

0.000844

AC:

AN:

24886

East Asian (EAS)

AF:

0.00

AC:

AN:

39288

South Asian (SAS)

AF:

0.00

AC:

AN:

79562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44102

Middle Eastern (MID)

AF:

0.000189

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

0.0000174

AC:

AN:

1091996

Other (OTH)

AF:

0.000136

AC:

AN:

58672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000112

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41554

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3590 of the ADGRV1 protein (p.Ser3590Cys). This variant is present in population databases (rs183319660, gnomAD 0.1%). 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: 505525). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Aug 18, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27460420)

May 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ADGRV1 c.10768A>T; p.Ser3590Cys variant (rs183319660) is reported in the literature in an individual affected with Usher syndrome who also carried a homozygous MYO7A variant (Bonnet 2016). This variant is reported in ClinVar (Variation ID: 505525), and is found in the Latino population with an allele frequency of 0.12% (38/30556 alleles, including a single homozygote) in the Genome Aggregation Database. The serine at codon 3590 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, however without functional studies, the effect on splicing is unknown. Due to limited information, the clinical significance of the p.Ser3590Cys variant is uncertain at this time. References: Bonnet et al. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. Eur J Hum Genet. 2016 Dec;24(12):1730-1738.

not specified

Uncertain:1

Dec 13, 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.Ser3590Cys variant in GPR98 has been previously reported in 1 individual w ith type 1 Usher syndrome explained by a homozygous variant in another gene (Bon net 2016). The p.Ser3590Cys variant has been reported in 0.1% (36/31300) of Lat ino chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs183319660). Computational prediction tools and conserva tion analyses suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. Furthermore, this variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to splicing. However , this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ser3590Cys variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

0.064

Eigen_PC

Benign

-0.0058

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

PhyloP100

1.5

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.15

Sift

Benign

0.043

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.54

MVP

0.59

MPC

0.32

ClinPred

0.22

GERP RS

3.1

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.24

gMVP

0.56

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over