NM_032119.4:c.12181G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_032119.4(ADGRV1):c.12181G>T(p.Val4061Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,611,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. V4061L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6O:1

Conservation

PhyloP100: 1.68

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052989393).

BP6

Variant 5-90763365-G-T is Benign according to our data. Variant chr5-90763365-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163601.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.12181G>T	p.Val4061Phe	missense	Exon 59 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.12197G>T		non_coding_transcript_exon	Exon 59 of 90

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.12181G>T	p.Val4061Phe	missense	Exon 59 of 90	ENSP00000384582.2
ADGRV1	ENST00000425867.3	TSL:5	c.1135G>T	p.Val379Phe	missense	Exon 7 of 38	ENSP00000392618.3
ADGRV1	ENST00000640464.1	TSL:5	n.2600G>T		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes

AF:

0.000662

AC:

100

AN:

151164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00130

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000712

AC:

177

AN:

248768

AF XY:

0.000719

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.00100

AC:

1464

AN:

1460212

Hom.:

Cov.:

AF XY:

0.000946

AC XY:

687

AN XY:

726304

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.0000671

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00127

AC:

1406

AN:

1110850

Other (OTH)

AF:

0.000514

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<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:

0.000661

AC:

100

AN:

151280

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

AN XY:

73844

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41202

American (AMR)

AF:

0.0000659

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

10364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00130

AC:

AN:

67882

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.000505

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00170

AC:

ExAC

AF:

0.000960

AC:

116

EpiCase

AF:

0.000767

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C (1)

Hearing impairment (1)

not specified (1)

Usher syndrome type 2C (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.98

PhyloP100

1.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Uncertain

0.015

Sift4G

Uncertain

0.024

Polyphen

0.93

Vest4

0.31

MVP

0.68

MPC

0.34

ClinPred

0.041

GERP RS

3.0

Varity_R

0.18

gMVP

0.57

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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