rs144618536

chr5-90745103-G-Achr5-90745103-G-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.10607G>A(p.Arg3536His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,613,714 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3536C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (5 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.193

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=0.006443411).
• BP6: Variant 5-90745103-G-A is Benign according to our data. Variant chr5-90745103-G-A is described in ClinVar as [Benign]. Clinvar id is 46250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90745103-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00309 (470/152186) while in subpopulation AFR AF= 0.0099 (411/41532). AF 95% confidence interval is 0.00911. There are 3 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.10607G>A	p.Arg3536His	missense_variant	51/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.10607G>A	p.Arg3536His	missense_variant	51/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152068 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00100 AC: 250 AN: 249104 Hom.: 1 AF XY: 0.000858 AC XY: 116 AN XY: 135122

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000733 AC: 1071 AN: 1461528 Hom.: 5 Cov.: 31 AF XY: 0.000675 AC XY: 491 AN XY: 727044

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000485

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00309 AC: 470 AN: 152186 Hom.: 3 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74398

Gnomad4 AFR AF: 0.00990

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000958 Hom.: 0

Bravo AF: 0.00378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0104 AC: 39

ESP6500EA AF: 0.00110 AC: 9

ExAC AF: 0.00125 AC: 151

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2012

Arg3536His in exon 51 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, has been identified in 0.12% (8/660) of Europea n American chromosomes and 1.1% (33/3068) of African American chromosomes in a b road population by the NHLBI Exome sequencing project (http://evs.gs.washington. edu/EVS/; rs144618536). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	6.1
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.43	N
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
Polyphen		0.045	B;B
Vest4		0.11
MVP		0.28
MPC		0.056
ClinPred		0.0045	T
GERP RS		4.3
Varity_R		0.022
gMVP		0.29

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: rs144618536; hg19: chr5-90040920;