NM_032119.4:c.7874G>A

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.7874G>A(p.Arg2625His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,486 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2625C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 10 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.70

Publications

10 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=0.007411778).

BP6

Variant 5-90694630-G-A is Benign according to our data. Variant chr5-90694630-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46381.

BS2

High Homozygotes in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.7874G>A	p.Arg2625His	missense	Exon 33 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.7890G>A		non_coding_transcript_exon	Exon 33 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.7874G>A	p.Arg2625His	missense	Exon 33 of 90	ENSP00000384582.2
ADGRV1	ENST00000509621.1	TSL:1	n.571G>A		non_coding_transcript_exon	Exon 1 of 26
ADGRV1	ENST00000640403.1	TSL:5	c.5165G>A	p.Arg1722His	missense	Exon 23 of 29	ENSP00000492531.1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00250

AC:

621

AN:

248280

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000813

Gnomad ASJ exome

AF:

0.0291

Gnomad EAS exome

AF:

0.00145

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00224

AC:

3267

AN:

1461230

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

1633

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33466

American (AMR)

AF:

0.000940

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

708

AN:

26106

East Asian (EAS)

AF:

0.000479

AC:

AN:

39692

South Asian (SAS)

AF:

0.00269

AC:

232

AN:

86214

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00183

AC:

2036

AN:

1111596

Other (OTH)

AF:

0.00346

AC:

209

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

187

373

560

746

933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00188

AC:

286

AN:

152256

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41542

American (AMR)

AF:

0.00164

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5184

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00276

Hom.:

Bravo

AF:

0.00191

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000493

AC:

ESP6500EA

AF:

0.00312

AC:

ExAC

AF:

0.00231

AC:

280

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (3)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.67

M_CAP

Benign

0.066

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.86

PhyloP100

2.7

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.9

REVEL

Benign

0.061

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.043

Vest4

0.10

MVP

0.64

MPC

0.058

ClinPred

0.017

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.54

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over