NM_032119.4:c.14309G>A

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.14309G>A(p.Arg4770His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,613,894 control chromosomes in the GnomAD database, including 38 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. R4770P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 36 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0830

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=0.0063824356).

BP6

Variant 5-90791138-G-A is Benign according to our data. Variant chr5-90791138-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46270.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 = 0.00364 (554/152280) while in subpopulation NFE AF = 0.00666 (453/68012). AF 95% confidence interval is 0.00615. There are 2 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.14309G>A	p.Arg4770His	missense	Exon 70 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.14325G>A		non_coding_transcript_exon	Exon 70 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.14309G>A	p.Arg4770His	missense	Exon 70 of 90	ENSP00000384582.2	Q8WXG9-1
ADGRV1	ENST00000638510.1	TSL:1	n.1576G>A		non_coding_transcript_exon	Exon 6 of 26
ADGRV1	ENST00000425867.3	TSL:5	c.3263G>A	p.Arg1088His	missense	Exon 18 of 38	ENSP00000392618.3	A0A1X7SBU6

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00337

AC:

838

AN:

248876

AF XY:

0.00341

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00645

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00578

AC:

8445

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

4103

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33478

American (AMR)

AF:

0.00107

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00724

AC:

8051

AN:

1111830

Other (OTH)

AF:

0.00346

AC:

209

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

472

944

1416

1888

2360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.00364

AC:

554

AN:

152280

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41556

American (AMR)

AF:

0.00131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00666

AC:

453

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00569

Hom.:

Bravo

AF:

0.00378

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00607

AC:

ExAC

AF:

0.00338

AC:

408

EpiCase

AF:

0.00562

EpiControl

AF:

0.00753

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.0

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.078

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.68

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.97

PhyloP100

-0.083

PrimateAI

Benign

0.19

PROVEAN

Benign

0.35

REVEL

Benign

0.088

Sift

Benign

0.70

Sift4G

Benign

0.65

Polyphen

0.0030

Vest4

0.052

MVP

0.055

MPC

0.056

ClinPred

0.0026

GERP RS

-7.1

PromoterAI

-0.0085

Neutral

(source)

Varity_R

0.015

gMVP

0.23

Mutation Taster

=96/4

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