5-90720961-C-T

Position:

chr5-90720961-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000405460.9(ADGRV1):c.9650C>T(p.Ala3217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,610,820 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3217A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0082 ( 13 hom., cov: 32)

Exomes 𝑓: 0.011 ( 113 hom. )

Consequence

ADGRV1
ENST00000405460.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 3.51

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 links:

LOC105379077 (HGNC:):

LOC105379077 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056247115).

BP6

Variant 5-90720961-C-T is Benign according to our data. Variant chr5-90720961-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158655.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=3}. Variant chr5-90720961-C-T is described in Lovd as [Benign]. Variant chr5-90720961-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00819 (1247/152178) while in subpopulation NFE AF= 0.0117 (798/68004). AF 95% confidence interval is 0.0111. There are 13 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.9650C>T	p.Ala3217Val	missense_variant	45/90	ENST00000405460.9	NP_115495.3
LOC105379077	XR_001742802.2 linkuse as main transcript	n.364-5152G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.9650C>T	p.Ala3217Val	missense_variant	45/90	1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.00820

AC:

1247

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00528

GnomAD3 exomes

AF:

0.00897

AC:

2230

AN:

248662

Hom.:

AF XY:

0.00894

AC XY:

1206

AN XY:

134918

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00355

Gnomad ASJ exome

AF:

0.00617

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00282

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0109

AC:

15912

AN:

1458642

Hom.:

113

Cov.:

AF XY:

0.0107

AC XY:

7763

AN XY:

725708

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.00363

Gnomad4 ASJ exome

AF:

0.00726

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00266

Gnomad4 FIN exome

AF:

0.0198

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.00880

GnomAD4 genome

AF:

0.00819

AC:

1247

AN:

152178

Hom.:

Cov.:

AF XY:

0.00810

AC XY:

603

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0215

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00671

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00237

AC:

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.00953

AC:

1152

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	This variant is associated with the following publications: (PMID: 22135276, 22334370, 21569298, 14740321) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADGRV1: BP4, BS1, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala3217Val in Exon 45 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (71/6670) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114137750). -

Usher syndrome type 2C

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Febrile seizures, familial, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

.;T

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

0.97

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.079

Sift

Benign

0.043

.;D

Sift4G

Uncertain

0.044

.;D

Polyphen

0.068

B;B

Vest4

0.26

MVP

0.61

MPC

0.074

ClinPred

0.013

GERP RS

5.8

Varity_R

0.11

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over