rs150549897

Positions:

• chr5-90712327-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032119.4(ADGRV1):​c.9083A>G​(p.Asn3028Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,557,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. N3028N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.94

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008969128).
• BP6: Variant 5-90712327-A-G is Benign according to our data. Variant chr5-90712327-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197473.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr5-90712327-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.9083A>G	p.Asn3028Ser	missense_variant	42/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9083A>G	p.Asn3028Ser	missense_variant	42/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000217 AC: 39 AN: 179420 Hom.: 0 AF XY: 0.000168 AC XY: 16 AN XY: 95336

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.0000372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000296

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.0000876 AC: 123 AN: 1404692 Hom.: 0 Cov.: 26 AF XY: 0.0000807 AC XY: 56 AN XY: 694276

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000265

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.000584

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74510

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000903

ESP6500AA AF: 0.00362 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 32

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2014	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2016

p.Asn3028Ser in exon 42 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.6% (18/2968) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150549897). -

ADGRV1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.19
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.55	.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.37	.;N
REVEL	Benign	0.090
Sift	Benign	0.41	.;T
Sift4G	Uncertain	0.034	.;D
Polyphen		0.028	B;B
Vest4		0.17
MVP		0.40
MPC		0.041
ClinPred		0.027	T
GERP RS		5.8
Varity_R		0.035
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150549897; hg19: chr5-90008144;