rs148171369

chr5-91072567-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_032119.4(ADGRV1):c.18273A>G(p.Ala6091=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,858 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (31 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10 O:1
• Conservation: PhyloP100: -0.889

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]

LUCAT1 (HGNC:48498): (lung cancer associated transcript 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-91072567-A-G is Benign according to our data. Variant chr5-91072567-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100602.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, not_provided=1, Uncertain_significance=1}. Variant chr5-91072567-A-G is described in Lovd as [Benign]. Variant chr5-91072567-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.889 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00403 (5895/1461514) while in subpopulation SAS AF= 0.00906 (781/86242). AF 95% confidence interval is 0.00853. There are 31 homozygotes in gnomad4_exome. There are 3124 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 11 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.18273A>G	p.Ala6091=	synonymous_variant	86/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.18273A>G	p.Ala6091=	synonymous_variant	86/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00407 AC: 1014 AN: 249030 Hom.: 11 AF XY: 0.00451 AC XY: 609 AN XY: 135080

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0100

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00403 AC: 5895 AN: 1461514 Hom.: 31 Cov.: 31 AF XY: 0.00430 AC XY: 3124 AN XY: 727034

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00906

Gnomad4 FIN exome AF: 0.00691

Gnomad4 NFE exome AF: 0.00395

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74484

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.00876

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00243

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00386

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ADGRV1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ala6091Ala in Exon 86 of GPR98: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.6% (38/6802) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs148171369). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Febrile seizures, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 19, 2014

- -

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
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.3
Dann	Benign	0.52

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

Other links and lift over

dbSNP: rs137853918; hg19: chr5-90368384; COSMIC: COSV67991306;