5-90619108-T-G

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.380T>G(p.Leu127Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,468,956 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 96 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1325 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.48

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067288876).

BP6

Variant 5-90619108-T-G is Benign according to our data. Variant chr5-90619108-T-G is described in ClinVar as Benign. ClinVar VariationId is 46321.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 = 0.0296 (4503/152262) while in subpopulation NFE AF = 0.0461 (3137/68012). AF 95% confidence interval is 0.0448. There are 96 homozygotes in GnomAd4. There are 2129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 96 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.380T>G	p.Leu127Arg	missense	Exon 4 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.479T>G		non_coding_transcript_exon	Exon 4 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.380T>G	p.Leu127Arg	missense	Exon 4 of 90	ENSP00000384582.2
ADGRV1	ENST00000640281.1	TSL:1	n.439T>G		non_coding_transcript_exon	Exon 4 of 7
ADGRV1	ENST00000508842.5	TSL:3	c.369+1155T>G		intron	N/A	ENSP00000425936.1

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4503

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0461

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0305

AC:

5556

AN:

182094

AF XY:

0.0303

show subpopulations

Gnomad AFR exome

AF:

0.00579

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.0448

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0414

AC:

54510

AN:

1316694

Hom.:

1325

Cov.:

AF XY:

0.0406

AC XY:

26335

AN XY:

649378

show subpopulations

African (AFR)

AF:

0.00596

AC:

174

AN:

29188

American (AMR)

AF:

0.0189

AC:

639

AN:

33752

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

317

AN:

23234

East Asian (EAS)

AF:

0.0000288

AC:

AN:

34766

South Asian (SAS)

AF:

0.00547

AC:

307

AN:

56110

European-Finnish (FIN)

AF:

0.0465

AC:

2239

AN:

48164

Middle Eastern (MID)

AF:

0.00501

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

0.0475

AC:

49063

AN:

1032094

Other (OTH)

AF:

0.0323

AC:

1743

AN:

54000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

1992

3984

5976

7968

9960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1920

3840

5760

7680

9600

<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:

0.0296

AC:

4503

AN:

152262

Hom.:

Cov.:

AF XY:

0.0286

AC XY:

2129

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00811

AC:

337

AN:

41566

American (AMR)

AF:

0.0235

AC:

359

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00600

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0499

AC:

529

AN:

10594

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0461

AC:

3137

AN:

68012

Other (OTH)

AF:

0.0261

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

226

452

678

904

1130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0414

Hom.:

481

Bravo

AF:

0.0266

TwinsUK

AF:

0.0494

AC:

183

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.00666

AC:

ESP6500EA

AF:

0.0459

AC:

373

ExAC

AF:

0.0293

AC:

3533

Asia WGS

AF:

0.00434

AC:

AN:

3466

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.95

PhyloP100

7.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.31

MPC

0.34

ClinPred

0.012

GERP RS

5.4

Varity_R

0.75

gMVP

0.86

Mutation Taster

=55/45

polymorphism (auto)

(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