rs201733037

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.7582C>T(p.Pro2528Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,972 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. P2528L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 23 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 2.80

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0103443265).

BP6

Variant 5-90694338-C-T is Benign according to our data. Variant chr5-90694338-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46377.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00273 (416/152322) while in subpopulation SAS AF = 0.0166 (80/4832). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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.7582C>T	p.Pro2528Ser	missense	Exon 33 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.7598C>T		non_coding_transcript_exon	Exon 33 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.7582C>T	p.Pro2528Ser	missense	Exon 33 of 90	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000509621.1	TSL:1	n.279C>T		non_coding_transcript_exon	Exon 1 of 26
ADGRV1	ENST00000640403.1	TSL:5	c.4873C>T	p.Pro1625Ser	missense	Exon 23 of 29	ENSP00000492531.1	A0A1W2PRC7

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00391

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00417

AC:

1038

AN:

249054

AF XY:

0.00484

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000696

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00368

AC:

5373

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

2935

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33472

American (AMR)

AF:

0.00239

AC:

107

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0156

AC:

1343

AN:

86258

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00321

AC:

3567

AN:

1111848

Other (OTH)

AF:

0.00364

AC:

220

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

391

782

1172

1563

1954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00273

AC:

416

AN:

152322

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

223

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41562

American (AMR)

AF:

0.00209

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

118

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:

0.00315

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00362

AC:

ExAC

AF:

0.00430

AC:

520

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00421

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (3)

Meniere disease (1)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

PhyloP100

2.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

REVEL

Benign

0.096

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.51

Vest4

0.20

MVP

0.64

MPC

0.13

ClinPred

0.012

GERP RS

5.9

Varity_R

0.15

gMVP

0.55

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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