rs72782753

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032119.4(ADGRV1):c.4939A>G(p.Ile1647Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,608,794 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1647M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 53 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.222

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=0.0047038198).

BP6

Variant 5-90674063-A-G is Benign according to our data. Variant chr5-90674063-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00496 (755/152260) while in subpopulation NFE AF = 0.00779 (530/68018). AF 95% confidence interval is 0.00724. There are 0 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 53 AD,AR 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.4939A>G	p.Ile1647Val	missense	Exon 23 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.5038A>G		non_coding_transcript_exon	Exon 23 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.4939A>G	p.Ile1647Val	missense	Exon 23 of 90	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000450321.2	TSL:1	n.*57A>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000492054.1	A0A1W2PR51
ADGRV1	ENST00000450321.2	TSL:1	n.*57A>G		3_prime_UTR	Exon 3 of 6	ENSP00000492054.1	A0A1W2PR51

Frequencies

GnomAD3 genomes

AF:

0.00496

AC:

755

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00781

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00461

AC:

1139

AN:

247216

AF XY:

0.00461

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00274

Gnomad NFE exome

AF:

0.00700

Gnomad OTH exome

AF:

0.00418

GnomAD4 exome

AF:

0.00653

AC:

9511

AN:

1456534

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

4688

AN XY:

724802

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33388

American (AMR)

AF:

0.00526

AC:

234

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.000614

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00231

AC:

198

AN:

85792

European-Finnish (FIN)

AF:

0.00268

AC:

143

AN:

53344

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00770

AC:

8535

AN:

1107854

Other (OTH)

AF:

0.00558

AC:

336

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

401

802

1203

1604

2005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.00496

AC:

755

AN:

152260

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

346

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41550

American (AMR)

AF:

0.00680

AC:

104

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00779

AC:

530

AN:

68018

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00635

Hom.:

Bravo

AF:

0.00507

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000819

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00428

AC:

517

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00749

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

4.9

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.054

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.71

M_CAP

Benign

0.010

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.99

PhyloP100

0.22

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.56

REVEL

Benign

0.074

Sift

Benign

0.56

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.12

MVP

0.16

MPC

0.044

ClinPred

0.0045

GERP RS

-10

Varity_R

0.027

gMVP

0.27

Mutation Taster

=94/6

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