5-90629222-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_032119.4(ADGRV1):c.1522A>C(p.Ile508Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00217 in 1,572,574 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 3 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 6.89

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: 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.

BP6

Variant 5-90629222-A-C is Benign according to our data. Variant chr5-90629222-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163563.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00221 (3134/1420384) while in subpopulation MID AF = 0.00593 (33/5564). AF 95% confidence interval is 0.00434. There are 3 homozygotes in GnomAdExome4. There are 1604 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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.1522A>C	p.Ile508Leu	missense	Exon 9 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.1621A>C		non_coding_transcript_exon	Exon 9 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.1522A>C	p.Ile508Leu	missense	Exon 9 of 90	ENSP00000384582.2
ADGRV1	ENST00000504142.2	TSL:5	n.288A>C		non_coding_transcript_exon	Exon 3 of 14
ADGRV1	ENST00000640109.1	TSL:5	n.1618A>C		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00214

AC:

484

AN:

226402

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.000266

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.00262

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00252

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00221

AC:

3134

AN:

1420384

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1604

AN XY:

702550

show subpopulations

African (AFR)

AF:

0.000407

AC:

AN:

31918

American (AMR)

AF:

0.00204

AC:

AN:

38180

Ashkenazi Jewish (ASJ)

AF:

0.00315

AC:

AN:

24442

East Asian (EAS)

AF:

0.00

AC:

AN:

39246

South Asian (SAS)

AF:

0.00196

AC:

153

AN:

77864

European-Finnish (FIN)

AF:

0.00375

AC:

196

AN:

52246

Middle Eastern (MID)

AF:

0.00593

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.00222

AC:

2426

AN:

1092340

Other (OTH)

AF:

0.00270

AC:

158

AN:

58584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

144

289

433

578

722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00183

AC:

279

AN:

152190

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41524

American (AMR)

AF:

0.00229

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00274

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68006

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00216

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.00294

AC:

ExAC

AF:

0.00212

AC:

256

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

ADGRV1-related disorder (1)

Retinal dystrophy (1)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.82

PhyloP100

6.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

REVEL

Benign

0.21

Sift

Benign

0.097

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MVP

0.65

MPC

0.066

ClinPred

0.040

GERP RS

3.1

Varity_R

0.24

gMVP

0.69

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 6

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