NM_032119.4:c.12592G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032119.4(ADGRV1):c.12592G>A(p.Val4198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,610,530 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4198L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 59 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 76 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.822

Publications

8 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: Orphanet, ClinGen
Usher syndrome type 2C
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001982808).

BP6

Variant 5-90777969-G-A is Benign according to our data. Variant chr5-90777969-G-A is described in ClinVar as Benign. ClinVar VariationId is 46262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

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.12592G>A	p.Val4198Met	missense	Exon 62 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.12608G>A		non_coding_transcript_exon	Exon 62 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.12592G>A	p.Val4198Met	missense	Exon 62 of 90	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000425867.3	TSL:5	c.1546G>A	p.Val516Met	missense	Exon 10 of 38	ENSP00000392618.3	A0A1X7SBU6
ADGRV1	ENST00000640464.1	TSL:5	n.3011G>A		non_coding_transcript_exon	Exon 19 of 21

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2675

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0597

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00468

AC:

1142

AN:

243834

AF XY:

0.00348

show subpopulations

Gnomad AFR exome

AF:

0.0614

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.000507

Gnomad EAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000525

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00203

AC:

2957

AN:

1458298

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1269

AN XY:

725040

show subpopulations

African (AFR)

AF:

0.0607

AC:

2029

AN:

33424

American (AMR)

AF:

0.00343

AC:

152

AN:

44296

Ashkenazi Jewish (ASJ)

AF:

0.000500

AC:

AN:

26016

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39626

South Asian (SAS)

AF:

0.000129

AC:

AN:

85492

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000417

AC:

463

AN:

1110210

Other (OTH)

AF:

0.00415

AC:

250

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

144

288

432

576

720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0176

AC:

2678

AN:

152232

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1253

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0596

AC:

2475

AN:

41532

American (AMR)

AF:

0.00857

AC:

131

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68008

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

131

262

393

524

655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00650

Hom.:

Bravo

AF:

0.0196

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0553

AC:

210

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.00545

AC:

658

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.076

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.098

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

PhyloP100

-0.82

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.31

REVEL

Benign

0.019

Sift

Benign

0.26

Sift4G

Benign

0.23

Polyphen

0.042

Vest4

0.15

MVP

0.12

MPC

0.048

ClinPred

0.0014

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.34

Mutation Taster

=99/1

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