rs74632023

chr5-90779052-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):c.13037C>T(p.Pro4346Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,612,880 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P4346P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (14 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114275515).
• BP6: Variant 5-90779052-C-T is Benign according to our data. Variant chr5-90779052-C-T is described in ClinVar as [Benign]. Clinvar id is 46265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90779052-C-T is described in Lovd as [Likely_benign]. Variant chr5-90779052-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00659 (1003/152086) while in subpopulation AFR AF= 0.0234 (969/41480). AF 95% confidence interval is 0.0221. There are 15 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.13037C>T	p.Pro4346Leu	missense_variant	64/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.13037C>T	p.Pro4346Leu	missense_variant	64/90	1	NM_032119.4	P1
ADGRV1	ENST00000425867.3	c.1991C>T	p.Pro664Leu	missense_variant	12/38	5
ADGRV1	ENST00000640464.1	n.3456C>T		non_coding_transcript_exon_variant	21/21	5
ADGRV1	ENST00000639431.1	c.265+102843C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 998 AN: 151968 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00191 AC: 474 AN: 248416 Hom.: 6 AF XY: 0.00150 AC XY: 202 AN XY: 134720

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000719 AC: 1050 AN: 1460794 Hom.: 14 Cov.: 31 AF XY: 0.000647 AC XY: 470 AN XY: 726702

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152086 Hom.: 15 Cov.: 32 AF XY: 0.00638 AC XY: 474 AN XY: 74352

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00140 Hom.: 3

Bravo AF: 0.00750

ESP6500AA AF: 0.0220 AC: 82

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00239 AC: 289

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	May 07, 2012	Pro4346Leu in Exon 64 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 2.5% (76/3026) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs74632023). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
Polyphen		1.0	D;D;.
Vest4		0.75
MVP		0.71
MPC		0.32
ClinPred		0.034	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74632023; hg19: chr5-90074869;