rs201733037

chr5-90694338-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 2.80

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 46377.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=5}. Variant chr5-90694338-C-T is described in Lovd as [Benign]. Variant chr5-90694338-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.7582C>T	p.Pro2528Ser	missense_variant	33/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.7582C>T	p.Pro2528Ser	missense_variant	33/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152204 Hom.: 4 Cov.: 33

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

GnomAD3 exomes AF: 0.00417 AC: 1038 AN: 249054 Hom.: 7 AF XY: 0.00484 AC XY: 654 AN XY: 135104

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 SAS exome AF: 0.0146

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.: 23 Cov.: 37 AF XY: 0.00404 AC XY: 2935 AN XY: 727104

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152322 Hom.: 4 Cov.: 33 AF XY: 0.00299 AC XY: 223 AN XY: 74484

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00300 Hom.: 3

Bravo AF: 0.00217

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00362 AC: 30

ExAC AF: 0.00430 AC: 520

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2019	This variant is associated with the following publications: (PMID: 26576034) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -
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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ADGRV1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Pro2528Ser in exon 33 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (27/6698) of European American chromosomes and 0.09% (3/3162) of African American chromosomes from a broad pop ulation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/ ). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jun 21, 2021

Digenic inheritance along with NM_000260.4:c.2507G>A(MYO7A) -

Usher syndrome type 2C Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.45	T
Polyphen		0.51	P;P;.
Vest4		0.20
MVP		0.64
MPC		0.13
ClinPred		0.012	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs201733037; hg19: chr5-89990155; COSMIC: COSV104434967;